Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same

ABSTRACT

This present disclosure relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receptor 1; VR1; TRPV1) antagonist; and a pharmaceutical composition containing the same. 
     The present disclosure provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, heart disease and so on.

TECHNICAL FIELD

The present disclosure relates to novel compounds, isomer thereof orpharmaceutically acceptable salts thereof as TRPV1 antagonist; and apharmaceutical composition containing the same.

BACKGROUND ART

The vanilloid receptor-1 (VR1, or transient receptor potentialvanilloid-1, TRPV1) is the receptor for capsaicin(8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient in hot peppers.The molecular cloning of TRPV1 was reported in 1997 (Caterina et al.,1997, Nature, 389, pp 816-824), which belongs to the TRP channel familyof non-selective cation channel. TRPV1 is activated or sensitized bystimuli such as capsaicin, resiniferatoxin, heat, acid, anandamide,lipid metabolites or the like; thus it plays a crucial role as amolecular integrator of noxious stimuli in mammals (Tominaga et al.,1998, Neuron, 21 pp 531-543; Hwang et al., 2000, PNAS, 97, pp6155-6160). The TRPV1 is highly expressed in primary afferent sensoryneurons, and also reportedly expressed in various organs and tissuessuch as bladder, kidney, lung, intestine, skin, central nervous system(CNS), and non-neuronal tissues (Mezey et al., 2000, PNAS, 97, pp3655-3660; Stander et al., 2004, Exp. Dermatol. 13, pp 129-139;Cortright et al., 2001, BBRC, 281, pp 1183-1189), and besides TRPV1protein is upregulated in painful disease conditions. Activation of theTRPV1 by endogenous/exogenous stimuli leads to not only transmission ofnoxious stimuli, but also liberation of neuropeptides such as substanceP, CGRP (Calcitonin Gene-Related Peptide) in the neurons, therebycausing neurogenic inflammation. TRPV 1 knock-out mice show normalresponses in a wide range of behavioural tests including noxiousmechanical and acute thermal stimuli, but exhibit little thermalhypersensitivity in inflammation states. (Caterina et al., 2000,Science, 288, pp 306-313; Davis et al., 2000, Nature, 405, pp 183-187;Karai et al., 2004, J. Clin. Invest., 113, pp 1344-1352).

As mentioned above, the TRPV1 knock-out mice exhibit reduced responsesto thermal or noxious stimuli, which has been supported by the effectsof TRPV 1 antagonists in various animal models of pain (Immke et al.,2006, Semin. Cell. Dev. Biol., 17(5), pp 582-91; Ma et al., 2007, ExpertOpin. Ther. Targets, 11(3), pp 307-20). The well-known TRPV1 antagonist,capsazepine, decreases hyperalgesia caused by physical stimuli inseveral models of inflammatory and neuropathic pain (Walker et al.,2003, JPET, 304, pp 56-62; Garcia-Martinez et al., 2002, PNAS, 99,2374-2379). In addition, treatment of the primary culture of afferentsensory neurons with the TRPV1 agonist, capsaicin etc., results indamage to nerve functions and furthermore death of nerve cells. TheTRPV1 antagonist exerts defense actions against such damage to nervefunctions and nerve cell death (Holzer P., 1991, PharmacologicalReviews, 43, pp 143-201; Mezey et al., 2000, PNAS, 97, 3655-3660). TheTRPV1 is expressed on sensory neurons distributed in all regions of thegastrointestinal tract and is highly expressed in inflammatory disorderssuch as irritable bowel syndrome and inflammatory bowel disease (Chan etal., 2003, Lancet, 361, pp 385-391; Yiangou et al., 2001, Lancet, 357,pp 1338-1339). In addition, activation of the TRPV1 stimulates sensorynerves, which in turn causes release of neuropeptides which are known toplay a critical role in pathogenesis of gastrointestinal disorders suchas gastro-esophageal reflux disease (GERD) and stomach duodenal ulcer(Holzer P., 2004, Eur. J. Pharmacol. 500, pp 231-241; Geppetti et al.,2004, Br. J. Pharmacol., 141, pp 1313-1320).

The TRPV1-expressing afferent nerves are abundantly distributed inairway mucosa, and bronchial hypersensitivity is very similar mechanismto hyperalgesia. Protons and lipoxygenase products, known as endogenousligands for the TRPV1, are well known as crucial factors responsible fordevelopment of asthma and chronic obstructive pulmonary diseases (Hwanget al., 2002, Curr. Opin. Pharmacol. pp 235-242; Spina et al., 2002,Curr. Opin. Pharmacol. pp 264-272). Moreover, it has been reported thatair-polluting substances which are a kind of asthma-causing substances,i.e., particulate matter specifically acts on the TRPV1 and such actionis inhibited by capsazepine (Veronesi et al., 2001, NeuroToxicology, 22,pp 795-810). Urinary bladder hypersensitiveness and urinary incontinenceare caused by various central/peripheral nerve disorders or injury, andTRPV1 expressed in afferent nerves and urothelial cells play animportant role in bladder inflammation. (Birder et al., 2001, PNAS, 98,pp 13396-13401). Further, TRPV1 knock-out mice are anatomically normalbut have higher frequency of low-amplitude, non-voiding bladdercontractions and reduced reflex voiding during bladder filling ascompared to wild type mice, which is thus indicating that the TRPV1affects functions of the bladder (Birder et al., 2002, Nat.Neuroscience, 5, pp 856-860). The TRPV1 is distributed in humanepidermal keratinocytes as well as in primary afferent sensory nerves(Denda et al., 2001, Biochem. Biophys. Res. Commun, 285, pp 1250-1252;Inoue et al., 2002, Biochem. Biophys. Res. Commun., 291, pp 124-129),and it is then involved in transmission of various noxious stimuli andpains such as skin irritation and pruritus, thereby having closecorrelation with etiology of dermatological diseases and disorders, suchas skin inflammation, due to neurogenic/non-neurogenic factors. This issupported by the report that the TRPV1 antagonist, capsazepine inhibitsinflammatory mediators in human skin cells (Southall et al., 2003, J.Pharmacol. Exp. Ther., 304, pp 217-222). Over recent years, evidence hasbeen accumulation on other roles of TRPV 1. TRPV 1 might be involved inthe blood flow/pressure regulation via sensory vasoactive neuropeptiderelease and in the regulation of plasma glucose levels or in thepathogenesis of type 1 diabetes (Inoue et al., Cir. Res., 2006, 99, pp119-31; Razavi et al., 2006, Cell, 127, pp 1123-35; Gram et al., 2007,Eur. J. Neurosci., 25, pp 213-23). Further, it is reported that TRPV1knock-out mice show less anxiety-related behavior than their wild typelittermates with no differences in locomotion (Marsch et al., 2007, J.Neurosci., 27(4), pp 832-9).

Based on the above-mentioned information, development of various TRPV1antagonists is under way, and some patents and patent applicationsrelating to TRPV 1 antagonists under development were published.(Szallasi et al., 2007, Nat. Rev. Drug Discov., 6, pp 357-72; Appendinoet al., 2006, Progress in Medicinal Chemistry, 44, pp 145-180; Rami etal., 2004, Drug Discovery Today: Therapeutic Strategies, 1, pp 97-104;Correll et al., 2006, Expert Opin. Ther. Patents, 16, pp 783-795; Kyleet al., 2006, Expert Opin. Ther. Patents, 16, pp 977-996)

Compounds of the present disclosure, are useful for prophylaxis andtreatment of diseases associated with the activity of TRPV1 (Nagy etal., 2004, Eur. J. Pharmacol. 500, 351-369) including but not limitedto, pain such as acute pain, chronic pain, neuropathic pain,post-operative pain, rheumatic arthritic pain, osteoarthritic pain,postherpetic neuralgia, neuralgia, headache, dental pain, pelvic pain,migraine, bone cancer pain, mastalgia and visceral pain (Petersen etal., 2000, Pain 88, pp 125-133; Walker et al., 2003, J. Pharmacol. Exp.Ther., 304, pp 56-62; Morgan et al., 2005, J. Orofac. Pain, 19, pp248-60; Dinis et al., 2005, Eur. Urol., 48, pp 162-7; Akerman et al.,2004, Br. J. Pharmcol., 142, pp 1354-1360; Ghilardi et al., 2005, J.Neurosci., 25, 3126-31; Gopinath et al., 2005, BMC Womens Health, 5,2-9); nerve-related diseases such as neuropathies, HIV-relatedneuropathy, nerve injury, neurodegeneration, and stroke (Park et al.,1999, Arch. Pharm. Res. 22, pp 432-434; Kim et al., 2005, J. Neurosci.25(3), pp 662-671); diabetic neuropathy (Kamei et al., 2001, Eur. J.Pharmacol. 422, pp 83-86); fecal urgency; irritable bowel syndrome (Chanet al., 2003, Lancet, 361, pp 385-391); inflammatory bowel disease(Yiangou et al., 2001, Lancet 357, pp 1338-1339); gastrointestinaldisorders such as gastro-esophageal reflux disease (GERD), stomachduodenal ulcer and Crohn's disease (Holzer P, 2004, Eur. J. Pharm., 500,pp 231-241; Geppetti et al., 2004, Br. J. Pharmacol., 141, pp1313-1320); respiratory diseases such as asthma, chronic obstructivepulmonary disease, cough (Hwang et al., 2002, Curr. Opin. Pharmacol. pp235-242; Spina et al., 2002, Curr. Opin. Pharmacol. pp 264-272; Geppettiet al., 2006, Eur. J. Pharmacol., 533, pp 207-214; McLeod et al., 2006,Cough, 2, 10); urinary incontinence (Birder et al., 2002, Nat.Neuroscience 5, pp 856-860); urinary bladder hypersensitiveness (Birderet al., 2001, PNAS, 98, pp 13396-13401); neurotic/allergic/inflammatoryskin diseases such as psoriasis, pruritus, prurigo and dermatitis(Southall et al., 2003, J. Pharmacol. Exp. Ther., 304, pp 217-222);irritation of skin, eye or mucous membrane (Tominaga et al., 1998,Neuron 21 pp 531-543); hyperacusis; tinnitus; vestibularhypersensitiveness (Balaban et al., 2003, Hear Res. 175, pp 165-70);cardiac diseases such as myocardial ischemia (Scotland et al., 2004,Circ. Res. 95, pp 1027-1034; Pan et al., 2004, Circulation 110, pp1826-1831); haemorrhagic shock (Akabori et al., 2007, Ann. Surg.,245(6), pp 964-70); hair growth-related disorders such as hirsutism,effluvium, alopecia (Bodó et al., 2005, Am. J. Patho. 166, pp 985-998;Bíró et al., 2006, J. Invest. Dermatol. pp 1-4); rhinitis (Seki et al.,2006, Rhinology, 44, pp 128-34); pancreatitis (Hutter et al., 2005,Pancreas, 30, pp 260-5); cystitis (Dinis et al., 2004, J. Neurosci., 24,pp 11253-63; Sculptoreanu et al., 2005, Neurosci. Lett. 381, pp 42-6);vulvodynia (Tympanidis et al., 2004, Eur. J. Pain, 8, pp 12-33);psychiatric disorders such as anxiety or fear (Marsch et al., 2007, J.Neurosci., 27(4), pp 832-9).

Compounds that are related to VR1 activities are discussed e.g. in WO02/61317, WO 02/090326, WO 02/16318, WO 02/16319, WO 03/053945, WO03/099284, WO 03/049702, WO 03/049702, WO 03/029199, WO 03/70247, WO04/07495, WO 04/72068, WO 04/035549, WO 04/014871, WO 04/024154, WO04/024710, WO 04/029031, WO 04/089877, WO 04/089881, WO 04/072069, WO04/111009, WO 05/03084, WO 05/073193, WO 05/051390, WO 05/049613, WO05/049601, WO 05/047280, WO 05/047279, WO 05/044802, WO 05/044786, WO06/097817, WO 06/098554, WO 06/100520, WO 06/101321, WO 06/102645, WO06/103503, WO 06/111346, WO 06/101321, WO 06/101318, WO 06/1113769, WO06/116563, WO 06/120481, WO 06/122250, WO 06/122799, WO 06/129164, WO06/51378, WO 06/95263, WO 07/42906, WO 07/45462, WO 07/50732, WO07/54474, WO 07/54480, WO 07/63925. WO 07/65663, WO 07/65888, WO07/67619, WO 07/67710, WO 07/67711, WO 07/67756, WO 07/67757,WO07/63925, WO07/65662, WO07/65663, WO07/65888, WO07/69773,US20070149517, or US20070149513.

More specifically, WO 06/101321 and WO 06/101318 relate to VR1modulators with a biphenyl partial structure. As a result of extensiveand intensive studies, the present inventors have consequentlysynthesized novel compounds having VR1 antagonistic activity. Said newcompounds have biphenylic structures, wherein one phenyl ring issubstituted in para position to its attachment position to the rest ofthe molecule with a trifluoromethyl group or a fluoro, and has at leastone additional substituent in ortho position (relative to saidattachment position). Compared to the specific compounds disclosed in WO06/101321 or WO 06/101318, which do not show this particular combinationof features, the present compounds show remarkable improvement of theirphysicochemical characteristics, such as metabolic stability orpharmacokinetic profiles.

Therefore, it is an object of the present disclosure to provide novelcompounds useful as a potent antagonist for a TRPV1, isomer thereof andpharmaceutically acceptable salts thereof; and a pharmaceuticalcomposition comprising the same.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure provides a novel compound of the followingformula (Ia), an isomer, or a pharmaceutically acceptable salt thereof:

wherein,

A is —C═C— or —CH—CH—;

R₁ is hydrogen, or C1-C3 alkyl;R₂ and R₃ are independently hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3alkoxy, halo(C1-C3)alkyl, (C2-C5)alkenyl, or (C2-C5)alkynyl;R₄ is halo(C1-C3)alkyl or halogen;R₅ is C2-C10 alkyl, C2-C10 alkoxy, C1-C5 alkoxy (C1-C5) alkoxy, C1-C5alkoxy (C1-C5) alkylamino, C2-C10 alkylamino, di(C1-C5 alkyl)amino,C3-C6 cycloalkylamino, C3-C6 cycloalkoxy, or(C3-C6)cycloalkyl(C1-C3)alkyloxy; andR₆ is hydrogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 alkylamino

The present disclosure also provides a novel compound of the followingformula (I), an isomer, or a pharmaceutically acceptable salt thereof:

wherein,R₁ is hydrogen, methyl, or ethyl;R₂ and R₃ are independently hydrogen, halogen, cyano, methyl, ethyl,methoxy, trifluoromethyl, vinyl, or acetylenyl;R₄ is trifluoromethyl or fluoro;R₅ is C2-C5 alkyl, C2-C5 alkoxy, C1-C2 alkoxy (C1-C3) alkoxy, C1-C2alkoxy (C1-C3) alkylamino, C2-C5 alkylamino, di(C1-C3 alkyl)amino, C3-C6cycloalkylamino, C3-C6 cycloalkoxy, or (C3-C6)cycloalkyl(C1-C3)alkyloxy;andR₆ is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 alkylamino.

Another aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; as described above wherein if R₅ is ethoxy, butoxy,pentoxy, (C3-C6)cycloalkoxy, or (C3-C6)cycloalkyl(C1-C3)alkyloxy, thenR₁ is methyl.

In another embodiment in the compounds of formula (Ia) or (I) asdisclosed further above, if R₅ is ethoxy, butoxy, or pentoxy, and R₄ issimultaneously fluoro, then R₁ is methyl.

In another embodiment in the compounds of formula (Ia) or (I) asdisclosed further above, if R₅ is ethoxy, butoxy, or pentoxy, then R₄ istrifluoromethyl. In this specific embodiment, R₁ is preferably methyl.

Another aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₁ is hydrogen; R₂ is halogen; and R₅ is C2-C4alkyl or C2-C4 alkylamino.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₁ is hydrogen; R₂ is fluoro; R₃ is hydrogen,fluoro, cyano, methyl, vinyl, or acetylenyl; R₄ is trifluoromethyl; R₅is C2-C4 alkyl or C2-C4 alkylamino; and R₆ is hydrogen.

Another aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₁ is hydrogen, methyl, ethyl, or preferablymethyl.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₁ is methyl; R₂ is halogen; and R₅ is C2-C4alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino.

Another aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof;

wherein,R₁ is methyl;R₂ is fluoro;R₃ is hydrogen, fluoro, vinyl, methyl, or acetylenyl;R₅ is C2-C4 alkyl, C2-C4 alkyloxy, or C2-C4 alkylamino; andR₆ is hydrogen or C1-C3 alkyl.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₂ and R₃ are independently hydrogen, fluoro,cyano, methyl, ethyl, methoxy, trifluoromethyl, vinyl, acetylenyl, orpreferably hydrogen, fluoro, cyano, methyl, vinyl, or acetylenyl.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₂ and R₃ are both fluoro.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₄ is fluoro, or preferably trifluoromethyl.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₅ and R₆ are both C1-C3 alkyl; or preferablymethyl, ethyl, or propyl; or more preferably propyl.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₆ is hydrogen.

One aspect of the present disclosure is a compound according to theabove formula (Ia) or (I), an isomer, or a pharmaceutically acceptablesalt thereof; wherein, R₅ is ethyl, propyl, isopropyl, n-butyl,isobutyl, sec-butyl, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, ethylamino, propylamino, isopropylamino, n-butylamino,isobutylamino, sec-butylamino, or cyclohexylmethoxy, provided that if R₅is ethoxy, butoxy, pentoxy, or cyclohexylmethoxy, then R₁ is methyl.

Another aspect of the present disclosure is a compound of the formula(Ia) or (I) as further described herein, an isomer, or apharmaceutically acceptable salt thereof, wherein, if R₁ is methyl orethyl, then the compound may be a pure enantiomer or may be a mixture ofthe (R) and (S)-enantiomer; and then, the C-atom to which R₁ is attachedis preferably in the (R)-configuration.

Another aspect of the present disclosure are compounds of the formula(Ia) or (I) as further described herein, an isomer, or apharmaceutically acceptable salt thereof wherein,

R₅ is C2-C5 alkyl, (C2-C5)alkyloxy, C1-C4 alkylamino, or(C3-C6)cycloalkylalkoxyoxy, wherein preferably,

R₅ is C2-C4 alkyl, (C2-C4)alkyloxy, or C2-C4 alkylamino; whereinparticularly preferably,

R₅ is C2-C4 alkyl, or C1-C3 alkylamino; wherein particularly preferably,

R₅ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ethoxy,propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, ethylamino,n-propylamino, isopropylamino, n-butylamino, isobutylamino,sec-butylamino, or cyclohexylmethoxy, wherein particularly preferably,

R₅ is C2-C4 alkyl, propoxy, isopropoxy, or C2-C4 alkylamino; whereineven more preferably,

R₅ is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, propoxy,isopropoxy, ethylamino, n-propylamino, isopropylamino, n-butylamino,isobutylamino, or sec-butylamino, wherein even more preferably,

R₅ is n-propyl, n-butyl, isobutyl, isopropoxy, sec-butoxy, ethylamino,n-propylamino, isopropylamino, n-butylamino, wherein more preferably,

R₅ is n-propyl, n-butyl, isobutyl, n-propoxy, ethylamino, propylamino,isopropylamino, n-butylamino, wherein even more preferably,

R₅ is propyl, butyl, isobutyl, ethylamino, propylamino, orisopropylamino, wherein even more preferably,

R₅ is propyl, butyl, ethylamino, propylamino, or isopropylamino.

Preferred examples of compounds according to the disclosure are selectedfrom the group consisting of;

-   N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Butylamino-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Cyano-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2,6-Dibutyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)-3-(2,6-Diethyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide,-   3-(2-Ethylamino-4-trifluoromethyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-5-methyl-benzyl)-acrylamide,-   N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-propyl]-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2-propoxy-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2-propylamino-phenyl)-acrylamide,-   (R)-3-(2-Butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)-3-(2-Butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[1-(3-fluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)-3-(2-sec-Butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)-3-(2-sec-Butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-4-fluoro-phenyl)-acrylamide,-   N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylamino-4-fluoro-phenyl)-acrylamide,-   (R)—N-(2-Fluoro-4-{1-[3-(2-propyl-4-trifluoromethyl-phenyl)-allylamino]-ethyl}-phenyl)-methanesulfonamide,-   (R)-3-(2-Butylamino-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   3-(2-Butylamino-4-fluoro-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isobutyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Cyclohexylmethoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2-propyl-phenyl)-acrylamide,-   N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-isopropylamino-4-trifluoromethyl-phenyl)-acrylamide,    and-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-propionamide.

Particularly preferred examples of compounds according to the disclosureare selected from the group consisting of

-   N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Butylamino-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3-Cyano-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2,6-Diethyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide,-   N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)-3-(2-Butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide,-   (R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[1-(3-fluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)-3-(2-sec-Butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)-3-(2-sec-Butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-4-fluoro-phenyl)-acrylamide,-   (R)—N-(2-Fluoro-4-{1-[3-(2-propyl-4-trifluoromethyl-phenyl)-allylamino]-ethyl}-phenyl)-methanesulfonamide,-   (R)-3-(2-Butylamino-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide,-   (R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isobutyl-4-trifluoromethyl-phenyl)-acrylamide,    and-   N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-isopropylamino-4-trifluoromethyl-phenyl)-acrylamide.

The compounds of the formula (Ia) or (I) of the present disclosure canchemically be synthesized by the following reaction schemes. However,these are given only for illustration of the disclosure and not intendedto limit to them.

The Scheme 1 shows a proposed process for synthesizing acrylamidecompound with various substituents. Substituted benzylamine (1) isreacted with phenylacrylic acid (2) to yield benzyl phenylacrylamide (3)using DMTMM {4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride} (Tetrahedron Lett., 1999, 40, 5327).

The Scheme 2 shows a proposed process for synthesizing acrylamidecompound (11) with various substituents. 4-Substituted 2-aminobenzoicacid (5), which is prepared by hydrogenation of 4-substituted2-nitrobenzoic acid (4), is converted to the corresponding alkylaminobenzoic acid (6) via reductive amination. The substituted benzoic acid(6) is converted to the corresponding Weinreb amide (7), which isreduced by lithium aluminum hydride to yield substituted benzaldehyde(8). The benzaldehyde (8) is converted to methyl phenyl acrylic ester(9) by Wittig reaction. The methyl phenyl acrylic ester (9) ishydrolyzed with lithium hydroxide to yield phenyl acrylic acid (10).

The phenyl acrylic acid (10) is reacted with substituted benzylamine (1)as shown in scheme 1 to yield benzyl phenylacrylamide (11).

The Scheme 3 shows a more efficient process for synthesizing alkylaminobenzoic acid (6) which is an intermediate to benzyl phenylacrylamide(11). One pot hydrogenation reaction of 4-substituted 2-nitrobenzoicacid (4) in the presence of an aldehyde and acetic acid replaces thetwo-step process including hydrogenation of 4 and reductive amination ofthe corresponding 2-aminobenzoic acid 5.

The Scheme 4 shows an alternative process for synthesizing Weinreb amide(7) which is an intermediate to benzyl phenylacrylamide (11).4-Substituted 2-nitrobenzoic acid (4) is converted to the correspondingWeinreb amide (12). Hydrogenation of the weinreb amide (12) followed byreductive amination with an aldehyde yields Weinreb amide (7).

The Scheme 5 shows a proposed process for synthesizing acrylamidecompound (20) with various substituents. 4-Substituted 2-hydroxybenzoicacid (13) is reacted with an alkyl halide and potassium carbonate toyield corresponding alkoxy benzoate (14), which is hydrolyzed withlithium hydroxide to give alkoxy benzoic acid (15). The substitutedbenzoic acid (15) is converted to benzyl phenylacrylamide (20) bysimilar processes used for benzyl phenylacrylamide (11) shown in Scheme2.

The Scheme 6 shows an alternative process for synthesizing methyl phenylacrylic ester (18) which is an intermediate to benzyl phenylacrylamide(20). 4-Substituted 2-hydroxybenzaldehyde (21) is converted tocorresponding methyl phenyl acrylic ester (22) by Wittig reaction, whichis reacted with an alkyl halide and potassium carbonate to yield methylphenyl acrylic ester (18).

The Scheme 7 shows a proposed process for synthesizing acrylamidecompound (25) with various substituents. 4-Trifluoromethyl iodobenzeneis converted to substituted phenyl acrylic acid methyl ester (23) bypalladium catalyzed coupling reaction. The phenyl acrylic acid methylester (23) is hydrolyzed with lithium hydroxide to yield phenyl acrylicacid (24). The phenyl acrylic acid (24) is reacted with substitutedbenzylamine (1) as described in Scheme 1 to yield benzylphenylacrylamide (25).

The Scheme 8 shows a proposed process for synthesizing acrylamidecompound (32) with various substituents. Substituted benzoyl chloride(26) is reacted with 2-amino-2-methyl-1-propanol in the present of abase, and the resulting adduct is treated with thionyl chloride followedby sodium hydroxide to afford dihydro-oxazole compound (27). Aftertreated with n-butyl lithium at low temperature, the compound 27 isreacted with an alkyl halide to give disubstituted dihydro-oxazole (28).The compound 28 is hydrolyzed with conc-HCl to the corresponding benzoicacid, which is converted to the Weinreb amide (29). After reducingcompound 29 with lithium aluminum hydride, the resulting aldehyde isconverted to the phenyl acrylic ester (30) under suitable Wittigreaction conditions. The acrylic ester (30) is hydrolyzed with lithiumhydroxide to yield the corresponding acrylic acid (31). Substitutedbenzylamine (1) is reacted with acrylic acid (31) as described in Scheme1 to yield benzyl phenylacrylamide (32).

The Scheme 9 shows a proposed process for synthesizing amide compound(33) with various substituents. Substituted acrylamide (3) is reducedwith Pd/C under hydrogen pressure to yield amide compound (33).

The present disclosure also provides to a compound of formula (Ia) or(I), an isomer thereof, or a pharmaceutically acceptable salt thereoffor use as a medicament.

In one embodiment, the present disclosure also provides a pharmaceuticalcomposition comprising a compound of formula (Ia) or (I), an isomerthereof, or a pharmaceutically acceptable salt thereof as an activeingredient and a pharmaceutically acceptable carrier.

In another embodiment, the present disclosure also provides acomposition comprising a compound of formula (Ia) or (I), an isomerthereof, or a pharmaceutically acceptable salt thereof; andpharmaceutically acceptable carrier for preventing or treating acondition associated with the pathological stimulation and/or aberrantexpression of vanilloid receptor.

In one preferred aspect, the present disclosure provides apharmaceutical composition comprising a compound of formula (Ia) or (I),an isomer thereof, or a pharmaceutically acceptable salt thereof, fortreating a condition selected from the group consisting of pain,inflammatory disease of the joints, neuropathies, HIV-relatedneuropathy, nerve injury, neurodegeneration, stroke, urinary bladderhypersensitivity including urinary incontinence, cystitis, stomachduodenal ulcer, irritable bowel syndrome (IBS) and inflammatory boweldisease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD),Crohn's disease, asthma, chronic obstructive pulmonary disease, cough,neurotic/allergic/inflammatory skin disease, psoriasis, pruritus,prurigo, irritation of skin, eye or mucous membrane, hyperacusis,tinnitus, vestibular hypersensitivity, episodic vertigo, cardiacdiseases such as myocardial ischemia, hair growth-related disorders suchas effluvium, alopecia, rhinitis, and pancreatitis.

In a particularly preferred aspect, the present disclosure relates tothe pharmaceutical composition comprising a compound of formula (Ia) or(I), an isomer thereof, or a pharmaceutically acceptable salt thereoffor treating pain as described above, wherein the pain is or isassociated with a condition selected from the group consisting ofosteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabeticneuropathic pain, post-operative pain, dental pain, non-inflammatorymusculoskeletal pain (including fibromyalgia, myofascial pain syndromeand back pain), visceral pain, migraine, and other types of headaches.

The present disclosure also provides a pharmaceutical compositioncomprising a compound of formula (Ia) or (I), an isomer thereof, or apharmaceutically acceptable salt thereof, which is characterized in thatit is adapted for oral administration.

In one aspect, the present disclosure relates to the use of a compoundof formula (Ia) or (I), an isomer thereof, or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament

In another aspect, the present disclosure relates to the use of acompound of formula (Ia) or (I), an isomer thereof, or apharmaceutically acceptable salt thereof for the preparation of amedicament for the prevention or treatment of a condition that isassociated with the aberrant expression and/or aberrant activation of avanilloid receptor.

In a preferred aspect, the present disclosure relates to the use of acompound of formula (Ia) or (I), an isomer thereof, or apharmaceutically acceptable salt thereof, in preparation of a medicamentfor the prevention or treatment of a condition that is selected from thegroup consisting of pain, inflammatory disease of the joints,neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration,stroke, urinary bladder hypersensitivity including urinary incontinence,cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) andinflammatory bowel disease (IBD), fecal urgency, gastro-esophagealreflux disease (GERD), Crohn's disease, asthma, chronic obstructivepulmonary disease, cough, neurotic/allergic/inflammatory skin disease,psoriasis, pruritus, prurigo, irritation of skin, eye or mucousmembrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodicvertigo, cardiac diseases such as myocardial ischemia, hairgrowth-related disorders such as effluvium, alopecia, rhinitis andpancreatitis.

In a particularly preferred aspect, the present disclosure relates tothe use of the compound of formula (Ia) or (I), an isomer thereof, forpreparing a medicament for preventing or treating pain as describedabove, wherein the condition is pain, which is or which is associatedwith a condition selected from the group consisting of osteoarthritis,rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain,post-operative pain, dental pain, non-inflammatory musculoskeletal pain(including fibromyalgia, myofascial pain syndrome and back pain),visceral pain, migraine, and other types of headaches.

In another aspect, the present disclosure relates to a method forinhibiting vanilloid ligand from binding to vanilloid receptor in apatient, comprising contacting cells expressing vanilloid receptor inthe patient with the compound of formula (Ia) or (I), an isomer thereof,or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure relates to a method forpreventing or treating a condition associated with the pathologicalstimulation and/or aberrant expression of vanilloid receptors.

In another aspect, the present disclosure also provides a method forpreventing or treating a condition selected from the group consisting ofpain, inflammatory disease of the joints, neuropathies, HIV-relatedneuropathy, nerve injury, neurodegeneration, stroke, urinary bladderhypersensitivity including urinary incontinence, cystitis, stomachduodenal ulcer, irritable bowel syndrome (IBS) and inflammatory boweldisease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD),Crohn's disease, asthma, chronic obstructive pulmonary disease, cough,neurotic/allergic/inflammatory skin disease, psoriasis, pruritus,prurigo, irritation of skin, eye or mucous membrane, hyperacusis,tinnitus, vestibular hypersensitivity, episodic vertigo, cardiacdiseases such as myocardial ischemia, hair growth-related disorders suchas effluvium, alopecia, rhinitis, and pancreatitis, which comprisesadministering to a mammal including a person in need thereof atherapeutically effective amount of the compound of formula (Ia) or (I),an isomer thereof, or a pharmaceutically acceptable salt thereof.

In a particularly preferred aspect, the present disclosure relates tothe method of treating pain by administering a compound of formula (Ia)or (I), an isomer thereof, or a pharmaceutically acceptable salt thereofas described above, wherein the pain is or is associated with acondition selected from the group consisting of osteoarthritis,rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain,post-operative pain, dental pain, non-inflammatory musculoskeletal pain(including fibromyalgia, myofascial pain syndrome and back pain),visceral pain, migraine, and other types of headaches

Hereinafter, the formulating methods and kinds of excipients will bedescribed, but the present disclosure is not limited to them.

A compound of formula (Ia) or (I), an isomer thereof or apharmaceutically acceptable salt thereof according to the presentdisclosure can be prepared as a pharmaceutical composition containingpharmaceutically acceptable carriers, adjuvants, diluents and the like.For instance, the compounds of the present disclosure can be dissolvedin oils, propylene glycol or other solvents which are commonly used toproduce an injection. Suitable examples of the carriers include, but notlimited to, physiological saline, polyethylene glycol, ethanol,vegetable oils, isopropyl myristate, etc. For topical administration,the compounds of the present disclosure can be formulated in the form ofointment or cream.

The compound according to the present disclosure may also be used in theforms of pharmaceutically acceptable salts thereof, and may be usedeither alone or in combination or in admixture with otherpharmaceutically active compounds.

The compounds of the present disclosure may be formulated intoinjections by dissolving, suspending or emulsifying in water-solublesolvent such as saline and 5% dextrose, or in water-insoluble solventssuch as vegetable oils, synthetic fatty acid glyceride, higher fattyacid esters and propylene glycol. The formulations of the disclosure mayinclude any of conventional additives such as dissolving agents,isotonic agents, suspending agents, emulsifiers, stabilizers andpreservatives.

The preferable dose level of the compounds according to the presentdisclosure depends upon a variety of factors including the condition andbody weight of the patient, severity of the particular disease, dosageform, and route and period of administration, but may appropriately bechosen by those skilled in the art. The compounds of the presentdisclosure are preferably administered in an amount ranging from 0.001to 100 mg/kg of body weight per day, and more preferably from 0.01 to 30mg/kg of body weight per day. Doses may be administered once a day, orseveral times a day with each divided portions. The compounds of thepresent disclosure are used in a pharmaceutical composition in an amountof 0.0001 10% by weight, and preferably 0.001 1% by weight, based on thetotal amount of the composition.

The pharmaceutical composition of the present disclosure can beadministered to a mammalian subject such as rat, mouse, domesticanimals, human being and the like via various routes. The methods ofadministration which may easily be expected include oral and rectaladministration; intravenous, intramuscular, subcutaneous, intrauterine,duramatral and intracerebroventricular injections.

DETAILED DESCRIPTION OF THE DEFINITIONS

When describing the compounds, pharmaceutical compositions containingsuch compounds, methods of using such compounds and compositions, anduse of such compounds and compositions, all terms used in the presentapplication shall have the meaning usually employed by a relevant personskilled in the art, e.g. by a medicinal chemists, pharmacist orphysician. By the way of example some definitions of specific groups aregiven below:

“Alkenyl” includes monovalent olefinically unsaturated hydrocarbylgroups being straight-chained or branched and having at least 1 doublebond. “Alkenyl” has preferably 2-5 carbon atoms (“C1-C5 alkenyl”), 2-4carbon atoms (“C2-C4 alkenyl”), or only 2-3 carbon atoms (“C2-C3alkenyl”). Particular alkenyl groups include ethenyl (—CH═CH₂),n-propenyl (—CH₂CH═CH₂), isopropenyl (C(CH₃)═CH₂), and the like. Apreferred “alkenyl” group is ethenyl (vinyl).

“Alkoxy” includes the group —OR wherein R is “alkyl” as defined furtherabove. Particular alkoxy groups include, by way of example, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, iso-butoxy,sec-butoxy, n-pentoxy, 1,2-dimethylbutoxy, and the like.

“Alkoxyalkoxy” refers to the group —OROR′, wherein R and R′ are the sameor different “alkyl” groups as defined further above.

“Alkoxyalkylamino” refers to the group —NH(ROR′), wherein R and R′ arethe same or different “alkyl” groups as defined further above.

“Alkyl” includes monovalent saturated aliphatic hydrocarbyl groups. Thehydrocarbon chain may be either straight-chained or branched. “Alkyl”has 1-6 carbon atoms (“C1-C6 alkyl”), and in some instances preferably1-5 carbon atoms (“C1-C5 alkyl”), 1-4 carbon atoms (“C1-C4 alkyl”), oronly 1-3 carbon atoms (“C1-C3 alkyl”). This term is exemplified bygroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, t-amyl, and the like.

“Alkynyl” includes acetylenically unsaturated hydrocarbyl groups beingstraight-chained or branched and having at least 1 triple bond.“Alkynyl” has preferably 2-6 carbon atoms (“C2-C6 alkynyl”), and in someinstances even more preferably 2-5 carbon atoms (“C1-C5 alkynyl”), 2-4carbon atoms (“C2-C4 alkynyl”), or only 2-3 carbon atoms (“C2-C3alkynyl”). A preferred alkynyl group is ethynyl (acetylenyl).

“Alkylamino” includes the group —NHR′, wherein R′ is alkyl group asdefined herein.

“Dialkylamino” includes the group —NR′R″, wherein R′ and R″ are alkylgroup as defined herein.

“Cycloalkyl” refers to cyclic saturated aliphatic hydrocarbyl groups.The numbers of C-atoms referenced in connection with a given cycloalkylgroup corresponds to the number of ring forming carbon atoms, e.g.“C3-C6 cycloalkyl” refers to a cycloalkyl with between three and sixring-forming C atoms. Examples of “cycloalkyl” are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl etc. If indicated, a “cycloalkyl”group may be unsubstituted or substituted with one or more alkyl groups,e.g. with C1-C6 alkyl groups, preferably with C1-C3 alkyl groups,particularly preferably with methyl groups. If a “cycloalkyl” carriesmore than one alkyl substituent these substituents may be attached tothe same or to different ring-forming carbon atoms.

“Cycloalkoxy” refers to the group —OR, wherein R is “cycloalkyl” groupas defined further above.

“Cycloalkylamino” refers to the group —NHR, wherein R is “cycloalkyl”group as defined further above.

“Cycloalkylalkoxy” refers to the group —OR—R′, wherein R is “alkyl”group and R′ is “cycloalkyl” group as defined further above. Examples of“cycloalkylalkoxy” are cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy, cyclopropylethoxy, etc.

“Cyano” refers to the radical —C≡N.

“Ethenyl” or “vinyl” refers to —CH═CH₂ which is also designated “vinyl”in the present application.

“Ethynyl” or “acetylenyl” refers to —C≡H.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo. Preferredhalo groups are either fluoro or chloro.

“Haloalkyl” includes an “alkyl” group as defined further above which issubstituted with one or more halogens which may be the same, e.g. intrifluoromethyl or pentafluoroethyl, or which may be different.

“Isomer” refers to especially optical isomers (for example essentiallypure enantiomers, essentially pure diastereomers, and mixtures thereof)as well as conformation isomers (i.e. isomers that differ only in theirangles of at least one chemical bond), position isomers (particularlytautomers), and geometric isomers (e.g. cis-trans isomers).

“Essentially pure”, e.g. in connection with enantiomers or diastereomersmeans at least about 90%, preferably at least about 95%, more preferablyat least about 97 or at least about 98%, even more preferably at leastabout 99%, and particularly preferably at least about 99.5% (w/w) of aspecified compound, e.g. a particular enantiomer or diastereomer.

“Pharmaceutically acceptable” means being devoid of substantial toxiceffects when used in doses usually employed in a medicinal dosage, andthereby being approvable or preferably being approved by a regulatoryagency of the Federal or a state government or being listed in the U.S.Pharmacopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of thedisclosure that is “pharmaceutically acceptable” as further definedherein, and that possesses the desired pharmacological activity of theparent compound. Such salts include: (1) acid addition salts, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2naphthalenesulfonicacid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like; or (2) salts formed when an acidic proton present in theparent compound is replaced.

“Pharmaceutically acceptable carrier” refers to a diluent, adjuvant,excipient or carrier with which a compound of the disclosure isadministered and which is “pharmaceutically acceptable” as furtherdefined herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Subject” includes humans and non-human mammals. The term “patient” isused interchangeably with “subject” herein and shall include humans andnon-human mammals unless specified otherwise.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” can vary depending on the compound, the disease and itsseverity, and the age, weight, etc., of the subject to be treated.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder. In yet another embodiment,“treating” or “treatment” refers to reducing, modifying or removing oneor more discernible symptom of a disease or disorder without modulatingthe cause of the underlying disease.

MODE FOR CARRYING OUT THE DISCLOSURE

The present disclosure is more specifically explained by followingexamples and experimental examples. However, it should be understoodthat the extent of the present disclosure is not limited to thefollowing examples and experimental examples

Example 1(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis of 2-amino-4-(trifluoromethyl)-benzoic acid

2-Nitro-4-trifluoromethyl-benzoic acid (3.07 g, 13.0 mmol) was stirredwith Pd/C under hydrogen atmosphere for 2 hrs. The reaction mixture wasfiltered with celite to remove Pd/C. The filterate was concentrated invacuo. The residue was extracted with CH₂Cl₂ (30 ml×3) and H₂O (30 ml).The combined organic layer was dried over MgSO₄ and then concentrated toyield title compound (2.66 g, 99%).

¹H NMR (300 MHz, DMSO-d₆): δ 7.82 (d, 1H), 7.02 (s, 1H), 7.05 (m, 1H),2.41 (br, 1H)

Step 2: Synthesis of 2-propylamino-4-(trifluoromethyl)-benzoic acid

2-Amino-4-(trifluoromethyl)benzoic acid (714 mg, 3.48 mmol),propionylaldehyde (0.27 ml, 3.74 mmol), acetic acid (3.49 mmol) andsodium triacetoxyborohydride (1.12 g, 5.25 mmol) were added in THF (40ml). The reaction mixture was stirred overnight. The reaction mixturewas quenched by adding sat. NaHCO₃ (50 ml). The aqueous mixture wasextracted with CH₂Cl₂ (30 ml×3). A combined organic layer was dried overMgSO₄, concentrated in vacuo, and purified with column chromatography toyield title compound (155 mg, 18%).

¹H NMR (300 MHz, CDCl₃): δ 8.04 (d, 1H, J=8.4 Hz), 6.89 (s, 1H), 6.79(d, 1H, J=8.1 Hz), 3.21 (t, 2H, J=7.2 Hz), 1.75 (m, 2H), 1.02 (t, 3H,J=7.8 Hz).

Step 3: Synthesis ofN-methoxy-N-methyl-2-propylamino-4-trifluoromethyl-benzamide

2-Propylamino-4-(trifluoromethyl)benzoic acid (147 mg, 0.594 mmol) inCH₂Cl₂ was reacted with N,O-dimethylhydroxy amine (82 mg), NMM (0.2 ml)and DMTMM (222 mg) at room temperature overnight. The reaction mixturewas quenched by adding H₂O (3 ml). The reaction solvent was removedunder reduced pressure. Water (30 ml) was added to the resultingresidue, which was extracted with ethylacetate (30 ml×3). The combinedorganic layer was washed with sat. NaHCO₃ solution (30 ml), 1N HClaqueous solution (30 ml) and brine (30 ml), and then dried over MgSO₄.The filterate was concentrated in vacuo. The residue was purified withcolumn chromatography to yield the title compound (98 mg, 57%).

¹H NMR (300 MHz, CDCl₃): δ 7.43 (d, 1H, J=7.8 Hz) 6.85 (s, 1H), 6.82 (d,1H), 3.56 (s, 3H), 3.34 (s, 3H), 3.10 (t, 2H, J=6.9 Hz), 1.71 (m, 2H),1.01 (t, 3H, J=6.9 Hz).

Step 4: Synthesis of 3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylicacid methyl ester

N-Methoxy-N-methyl-2-propylamino-4-trifluoromethyl-benzamide (98.3 mg,0.339 mmol) was reacted with 1M lithium aluminum hydride (0.6 ml) in THF(20 ml) at −40° C. for 1 hr. The reaction mixture was quenched by addingsaturated potassium hydrogen sulfate solution. The mixture was stirredfor 30 min. The reactions solvent was removed in vacuo. Water (30 ml)was added to the resulting residue, which was extracted with CH₂Cl₂ (30ml×3). The combined organic layer was dried over MgSO₄ and concentratedin vacuo to yield 2-propylamino-4-trifluoromethyl-benzaldehyde (78 mg).2-Propylamino-4-trifluoromethyl-benzaldehyde in toluene was reacted withmethyl (triphenylphosphoranylidene) acetate (137 mg) at 100° C.overnight. The reaction solvent was removed in vacuo. Water (30 ml) wasadded to the resulting residue, which was extracted with ethyl acetate(30 ml×3). The combined organic layer was dried over MgSO₄ and filtered.The filterate was concentrated in vacuo and purified with columnchromatography to yield title compound (67 mg, 69%).

¹H NMR (300 MHz, CDCl₃): δ 7.76 (d, 1H, J=15.9 Hz), 7.41 (d, 1H, J=8.1Hz), 6.92 (d, 1H, J=8.7 Hz), 6.84 (s, 1H), 6.38 (d, 1H, J=15.6 Hz), 3.82(s, 3H), 3.17 (m, 2H), 1.70 (m, 2H), 1.04 (t, 3H, J=7.8 Hz).

Step 5: Synthesis of 3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylicacid

3-(2-Propylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester(67.3 mg, 0.234 mmol) was reacted with aqueous 1N LiOH solution (5 ml)in THF/CH₃OH (10 ml/5 ml) for 1 hr. The reaction solvent removed invacuo. Water (30 ml) was added to the resulting residue, which wasneutralized with 1N HCl solution, an then extracted with ethyl acetate(30 ml×3). The combined organic layer was dried over MgSO₄ andconcentrated in vacuo to yield title compound (55 mg, 0.201 mmol, 86%).

¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, 1H, J=15.6 Hz), 7.48 (d, 1H, J=7.5Hz), 6.82 (s, 1H), 6.79 (s, 1H), 6.36 (d, 1H, J=15.6 Hz), 3.10 (t, 2H,J=6.9 Hz), 1.75 (m, 2H), 0.97 (t, 3H, J=7.5 Hz)

Step 6: Synthesis of(R)—N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(70 mg, 0.24 mmol) in THF was reacted with3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid (55 mg, 0.20mmol), NMM (0.2 ml) and DMTMM (86 mg, 0.34 mmol) at room temperatureovernight. The reaction mixture was quenched by adding H₂O. The reactionsolvent was removed in vacuo. Water (30 ml) was added to the resultingresidue, which was extracted with ethyl acetate (30 ml×3). The combinedorganic layer was dried over MgSO₄. The filterate was concentrate underreduced pressure and purified with column chromatography to yield thetitle compound (35 mg, 59%).

¹H NMR (300 MHz, CDCl₃): δ 7.79 (d, 1H, J=15 Hz), 7.37 (d, 1H, J=7.8Hz), 6.96 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 6.48(br, 1H), 6.33 (d, 1H, J=15.3 Hz), 5.93 (d, 1H, J=7.2 Hz), 5.15 (t, 1H,J=7.2 Hz), 3.19 (s, 3H), 3.14 (t, 2H, J=7.2 Hz), 1.70 (m, 2H), 0.97 (t,3H, J=7.5 Hz)

ESI [M−H]⁻: 504

Example 2N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (84mg, 0.308 mmol) was reacted with3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid (67 mg, 0.245mmol), NMM (0.4 ml) and DMTMM (121 mg) to give the title compound (62mg, 52%).

¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 1H, J=15.6 Hz), 7.33 (d, 1H, J=7.8Hz), 6.95 (d, 1H, J=8.4 Hz), 6.84 (d, 1H, J=8.1 Hz), 6.79 (s, 1H), 6.30(d, 1H, J=15.6 Hz), 6.03 (br, 1H), 4.59 (br, 1H, J=6.9 Hz), 4.50 (d, 2H,J=6.0 Hz), 3.16 (s, 3H), 3.12 (t, 2H, J=7.2 Hz), 1.64 (m, 2H), 0.96 (t,3H, J=7.5 Hz)

Example 3(R)-3-(2-Butylamino-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

(R)—N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (25 mg, 0.09 mmol) was reacted with3-(2-butylamino-4-trifluoromethyl-phenyl)-acrylic acid (25 mg, 0.09mmol) to give the title compound (15 mg, 32%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, CDCl₃): δ 7.75 (d, 1H, J=15.3 Hz), 7.37 (d, 1H, J=8.4Hz), 7.00 (m, 2H), 6.90 (d, 1H, J=8.4 Hz), 6.83 (s, 1H), 6.33 (d, 1H,J=15.3 Hz), 6.12 (s, 1H), 5.83 (d, 1H, J=7.8 Hz), 5.18 (m, 1H), 4.18(bs, 1H), 3.21 (s, 3H), 3.17 (m, 2H), 1.48 (m, 5H), 0.97 (t, 3H, J=7.5Hz).

ESI [M−H]⁻: 518

Example 4N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis of 2-propoxy-4-trifluoromethyl-benzoic acid propylester

2-Hydroxy-4-trifluoromethyl-benzoic acid (673 mg, 3.26 mmol) was reactedwith propylbromide (0.85 ml) and K₂CO₃ (1.42 g) in DMF (15 ml) at 65° C.overnight. The reaction mixture was quenched by adding 10 ml of H₂O. Themixture was extracted with ethylacetate (30 ml×3). A combined organiclayer was washed with H₂O (50 ml×6) and brine (50 ml), and dried overMgSO₄. The filterate was concentrated in vacuo to yield title compound(908 mg, 99%)

¹H NMR (300 MHz, CDCl₃): δ 7.83 (d, 1H, J=8.1 Hz), 7.21 (d, 1H, J=8.1Hz), 7.15 (s, 1H), 4.28 (t, 2H, J=6.9 Hz), 4.03 (t, 2H, J=6.3 Hz), 1.88(m, 2H), 1.82 (m, 2H), 1.07 (m, 6H)

Step 2: Synthesis of 2-propoxy-4-trifluoromethyl-benzoic acid

2-Propoxy-4-trifluoromethyl-benzoic acid propyl ester (957 mg, 3.44mmol) was reacted with 1N LiOH (10 ml) at room temperature for 4 hrs.The reaction solvent was removed in vacuo. Water (30 ml) was added tothe resulting residue, which was neutralized with 1 N aqueous HClsolution. The aqueous mixture was extracted with ethylacetate (30 ml×3).A combined organic layer was dried over MgSO₄, and concentrated in vacuoto yield quantitatively title compound.

¹H NMR (300 MHz, CDCl₃): δ 8.32 (d, 1H, J=7.8 Hz), 7.40 (d, 1H, J=8.1Hz), 7.16 (s, 1H), 4.28 (t, 2H, J=6.6 Hz), 1.98 (m, 2H), 1.26 (m, 3H)

Step 3: Synthesis ofN-methoxy-N-methyl-2-propoxy-4-trifluoromethyl-benzamide

2-Propoxy-4-(trifluoromethyl)benzoic acid (457 mg, 1.93 mmol) in THF wasreacted with N,O-dimethylhydroxy amine (378 mg), NMM (0.65 ml) and DMTMM(947 mg) at room temperature overnight. The reaction solvent was removedin vacuo. Water (30 ml) was added to the resulting residue, which wasextracted with ethyl acetate (30 ml×3). The combined organic layer waswashed with 1 M NaHCO₃ (30 ml), 1N HCl (30 ml) and brine (30 ml) anddried over MgSO₄. The filterate was purified with column chromatography(Hex/EtOAc=4/1) to yield the title compound (277 mg, 49%).

¹H NMR (300 MHz, CDCl₃): δ 7.36 (d, 1H, J=7.8 Hz), 7.25 (d, 1H, J=8.1Hz), 7.12 (s, 1H), 4.01 (t, 2H, J=6.3 Hz), 3.46 (s, 3H), 3.35 (br, 3H),1.83 (m, 2H), 1.03 (t, 3H, J=6.9 Hz)

Step 4: Synthesis of 2-propoxy-4-trifluoromethyl-benzaldehyde

N-Methoxy-N-methyl-2-propoxy-4-trifluoromethyl-benzamide (277 mg) in THFwas reacted with 1 M LAH (1 ml) on −50° C. for 1 hr. The reactionmixture was quenched by adding aqueous potassium hydrogen sulfate (5ml). The mixture was stirred for 30 min. The reaction solvent wasremoved in vacuo. Water (30 ml) was added to the resulting residue,which was extracted with ethyl acetate (30 ml×3). The combined organiclayer was washed with brine (30 ml) and dried over MgSO₄ andconcentrated in vacuo to yield title compound (232 mg, 100%).

¹H NMR (300 MHz, CDCl₃): δ 10.54 (s, 1H), 7.93 (d, 1H, J=8.1 Hz), 7.27(d, 1H, J=8.1 Hz), 7.21 (s, 1H), 4.10 (t, 2H, J=6.6 Hz), 1.91 (m, 2H),1.10 (t, 3H, J=7.2 Hz)

Step 5: Synthesis of 3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylic acidmethyl ester

2-Propoxy-4-trifluoromethyl-benzaldehyde (232 mg, 1 mmol) in toluene wasreacted with methyl (triphenylphosphoranylidene)acetate (382 mg, 1.14mmol) at 110° C. overnight. The reaction solvent was removed underreduced pressure. Water (30 ml) was added to the resulting residue,which was extracted with ethyl acetate (30 ml×3). The combined organiclayer was washed with brine (30 ml) and dried over MgSO₄. The filteratewas purified with column chromatography to yield title compound (198 mg,69%).

¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, 1H, J=16.2 Hz), 7.58 (d, 1H, J=8.1Hz), 7.21 (m, 1H), 7.11 (s, 1H), 6.60 (d, 1H, J=16.2 Hz), 4.04 (t, 2H,J=6.0 Hz), 3.81 (s, 3H), 1.91 (m, 2H), 1.09 (t, 3H, J=7.5 Hz).

Step 6: Synthesis of 3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylic acid

3-(2-Propoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (198mg) was reacted with 1N LiOH (5 ml) in THF (10 ml) and CH₃OH (5 ml) for1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) wasadded to the resulting residue, which was neutralized with 1N HClsolution. The mixture was extracted with ethyl acetate (30 ml×3). Thecombined organic layer was dried over MgSO₄. The filterate wasconcentrated in vacuo to yield title compound (136 mg, 72%).

¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, 1H, J=16.2 Hz), 7.71 (d, 1H, J=8.4Hz), 7.21 (m, 1H), 7.12 (s, 1H), 6.59 (d, 1H, J=16.2 Hz), 4.04 (t, 2H,J=6.0 Hz), 1.78 (m, 2H), 1.06 (t, 3H, J=7.5 Hz)

Step 7: Synthesis ofN-(3,5-difluoro-4-methanesulfonylamino-benzyl)-3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (78mg, 0.286 mmol) in THF was reacted with3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylic acid (67 mg, 0.246 mmol),NMM (0.2 ml) and DMTMM (86 mg) to give the title compound (92 mg, 76%)after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, 1H, J=15.9 Hz), 7.52 (d, 1H, J=8.4Hz), 7.21 (m, 1H), 7.06 (s, 1H), 6.93 (d, 1H, J=7.8 Hz), 6.55 (d, 1H,J=16.2 Hz), 5.96 (br, 1H), 4.51 (d, 2H, J=6.0 Hz), 4.00 (t, 2H, J=6.0Hz), 3.16 (s, 3H), 1.87 (m, 2H), 1.04 (t, 3H, J=7.5 Hz)

ESI [M−H]⁻: 505

Example 5(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(81 mg, 0.28 mmol) was reacted with3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylic acid (68 mg, 0.25 mmol),NMM (0.2 ml) and DMTMM (86 mg) at room temperature overnight to yieldthe title compound (89 mg, 72%) after column chromatography(Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.92 (d, 1H, J=15.6 Hz), 7.55 (d, 1H, J=7.8Hz), 7.19 (d, 1H, J=10.8 Hz), 7.10 (s, 1H), 6.99 (d, 1H, J=8.7 Hz), 6.55(d, 1H, J=15.9 Hz), 5.99 (br, 1H), 5.78 (br, 1H), 5.19 (m, 1H), 4.03 (t,2H, J=6.6 Hz), 3.20 (s, 3H), 1.90 (m, 2H), 1.08 (t, 3H, J=7.5 Hz)

Example 6(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis of 3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylicacid methyl ester

In a 100 ml flask, 4-iodobenzotrifluoride (1 g, 3.68 mmol) was dissolvedin 10 ml DMF, and Pd(OAc)₂ (165 mg, 0.2 eq), K₂CO₃ (2.54 g, 5.0 eq),KOAc (1.8 g, 5.0 eq), norbonylene (692 mg, 1.0 eq), methyl acrylate(0.33 ml, 1.0 eq), and iodopropane (3.75 g, 6.0 eq) were addedstepwisely at room temperature. The resulting reaction mixture wasstirred for 3 days. After the completion of the reaction, the Na₂S₂O₃solution was poured into the reaction mixture, which was stirred for 30minutes, extracted with EtOAc 50 ml (3 times), and dried with anh.MgSO₄.The organic layer was filtered, concentrated in vacuo, and purified withcolumn chromatography (Hexane:EtOAc=8:1) to give the title compound(0.343 g, 30%).

¹H NMR (300 MHz, CDCl₃): δ 7.83 (d, 1H, J=16.2 Hz), 7.31 (s, 2H), 6.01(d, 1H, J=16.2 Hz), 3.84 (s, 3H), 2.62 (m, 4H), 1.58 (m, 4H), 0.94 (m,6H).

Step 2: Synthesis of 3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylicacid

3-(2,6-Dipropyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (343mg) was reacted with 1N LiOH (5 ml) in THF (10 ml) and CH₃OH (5 ml) for1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) wasadded to the resulting residue, which was neutralized with 1N HClsolution. The mixture was extracted with ethyl acetate (30 ml×3). Thecombined organic layer was dried over MgSO₄. The filterate wasconcentrated in vacuo to yield title compound (250 mg, 82%).

Step 3: Synthesis of(R)—N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (250 mg, 0.87 mmol) was reacted with3-(2,6-dipropyl-4-trifluoromethyl-phenyl)-acrylic acid (261 mg, 0.87mmol) to give the title compound (181 mg, 39%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.70 (t, 1H, J=7.5 Hz), 7.56(d, 1H, J=15.9 Hz), 7.42 (s, 2H), 7.15 (m, 2H), 6.23 (d, 1H, J=16.2 Hz),5.05 (m, 1H), 3.05 (s, 3H), 2.61 (m, 4H), 1.51 (m, 4H), 1.41 (d, 3H,J=7.2 Hz), 0.88 (m, 6H).

ESI [M−H]⁻: 531

Example 7(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis of 2-ethoxy-4-trifluoromethyl-benzoic acid

2-Hydroxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.82 mmol) was reactedwith ethyliodide (2.2 eq) and K₂CO₃ (1.69 g) in DMF solution. Thereaction mixture was quenched by adding H₂O. The mixture was extractedwith ethyl acetate (40 ml×3). A combined organic layer was washed satNaHCO₃ solution (30 ml), H₂O (40 ml×5), and brine, and then dried overMgSO₄. The filterate was concentrated in vacuo to yield2-ethoxy-4-trifluoromethyl benzoic acid ethyl ester. The ester obtainedabove was reacted with 1 N LiOH (15 ml) in THF and CH₃OH cosolvent for 2hrs as described above to yield title compound (1.20 g, 88%)

¹H NMR (300 MHz, CDCl₃): δ 8.32 (d, 1H, J=8.1 Hz), 7.40 (d, 1H, J=8.1Hz), 7.26 (s, 1H), 4.40 (q, 2H, J=6.9 Hz), 1.62 (t, 3H, J=6.9 Hz)

Step 2: Synthesis ofN-methoxy-N-methyl-2-ethoxy-4-trifluoromethyl-benzamide

2-Ethoxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.12 mmol) was reactedwith N,O-dimethylhydroxy amine (609 mg), NMM (0.95 ml) and DMTMM (1.47mg) as described above to give the title compound (1.04 g, 73%) aftercolumn chromatography (Hex/EtOAc=5/1).

¹H NMR (300 MHz, CDCl₃): δ 7.40 (br, 1H), 7.23 (br, 1H), 7.10 (s, 1H),4.13 (t, 2H, J=6.3 Hz), 3.49 (s, 3H), 3.37 (br, 3H), 1.42 (t, 3H, J=6.9Hz)

Step 3: Synthesis of 2-ethoxy-4-trifluoromethyl-benzaldehyde

N-Methoxy-N-methyl-2-ethoxy-4-trifluoromethyl-benzamide (1.04 g) wasreacted with 1 M LAH (1 ml) at −40° C. for 2 hrs as described above toyield title compound (729 mg, 65%)

¹H NMR (300 MHz, CDCl₃): δ 10.52 (s, 1H), 7.93 (d, 1H, J=8.1 Hz), 7.27(d, 1H, J=8.1 Hz), 7.20 (s, 1H), 4.21 (q, 2H, J=6.6 Hz), 1.52 (t, 3H,J=6.9 Hz)

Step 4: Synthesis of 3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acidmethyl ester

2-Ethoxy-4-trifluoromethyl-benzaldehyde (729 mg, 3.34 mmol) was reactedwith methyl (triphenylphosphoranylidene)acetate (1.45 g, 4.34 mmol) at110° C. overnight as described above to yield title compound (476.5 mg,52%).

¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, 1H, J=16.5 Hz), 7.58 (d, 1H, J=16.2Hz), 7.58 (d, 1H, J=7.8 Hz), 7.21 (m, 1H), 7.11 (s, 1H), 6.60 (d, 1H,J=15.9 Hz), 4.14 (q, 2H, J=6.9 Hz), 3.82 (s, 3H), 1.58 (t, 3H, J=7.5 Hz)

Step 5: Synthesis of 3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid

3-(2-Ethoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (477 mg,1.74 mmol) was reacted with 1N LiOH (7.5 ml) in THF and CH₃OH for 1.5hrs as described above to yield title compound (440 mg, 97%)

¹H NMR (300 MHz, CDCl₃): δ 8.07 (d, 1H, J=16.2 Hz), 7.62 (d, 1H, J=8.1Hz), 7.26 (m, 1H), 7.12 (s, 1H), 6.62 (d, 1H, J=16.2 Hz), 4.16 (q, 2H,J=6.9 Hz), 1.52 (t, 3H, J=6.9 Hz)

Step 6: Synthesis of(R)—N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(70 mg, 0.24 mmol) was reacted with3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid (59 mg, 0.22 mmol),NMM (0.2 ml) and DMTMM (73 mg, 0.26 mmol) to give the title compound (77mg, 69%) after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.94 (d, 1H, J=15.9 Hz), 7.56 (d, 1H, J=8.1Hz), 7.19 (d, 1H, J=8.1 Hz), 7.09 (s, 1H), 6.75 (d, 1H, J=8.1 Hz), 6.57(d, 1H, J=15.9 Hz), 6.08 (br, 1H), 5.87 (d, 1H, J=7.8 Hz), 5.20 (t, 1H)4.13 (q, 2H, J=6.9 Hz), 3.20 (s, 3H), 1.52 (t, 3H, J=7.5 Hz)

ESI [M−H]⁻: 491

Example 8N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (60mg, 0.22 mmol) was reacted with3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid (52 mg, 0.20 mmol),NMM (0.2 ml) and DMTMM (73 mg, 0.25 mmol) at room temperature to yieldthe title compound (50 mg, 52%) after column chromatography(Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.94 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=7.8Hz), 7.21 (d, 1H, J=7.8 Hz), 7.11 (s, 1H), 7.00 (m, 2H), 6.77 (d, 1H,J=8.4 Hz), 6.62 (d, 1H, J=15.9 Hz), 6.03 (br, 1H), 4.56 (d, 2H, J=6.0Hz), 4.15 (q, 2H, J=7.2 Hz), 3.21 (s, 3H), 1.48 (t, 3H, J=7.2 Hz)

Example 9(R)—N-[1-(3-Fluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-(4-Aminoethyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (60mg, 0.22 mmol) was reacted with3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid (51 mg, 0.19 mmol),NMM (0.2 ml) and DMTMM (72 mg) at room temperature overnight to yieldthe title compound (62 mg, 0.13 mmol, 68%) after column chromatography(Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.91 (d, 1H, J=15.6 Hz), 7.55 (m, 1H), 7.44(m, 1H), 7.15 (d, 1H, J=9.0 Hz), 7.08 (s, 1H), 6.93 (m, 1H), 6.55 (d,1H, J=15.0 Hz), 5.95 (br, 1H), 5.87 (d, 1H, J=7.8 Hz), 5.21 (t, 1H) 4.14(q, 2H, J=6.9 Hz), 3.02 (s, 3H), 1.53 (t, 3H, J=7.5 Hz)

Example 10(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis ofN-methoxy-N-methyl-2-nitro-4-trifluoromethyl-benzamide

2-Nitro-4-trifluoromethyl-benzoic acid (2.753 mg, 11.7 mmol) in THF wasreacted with N,O-dimethylhydroxy amine (1.277 g, 13.1 mmol), NMM (3 ml)and DMTMM (3.34 g) at room temperature overnight. The reaction mixturewas quenched by adding H₂O. The mixture was extracted with ethyl acetate(50 ml×3). The combined organic layer was washed 1M NaHCO₃ (50 ml×2), 3%HCl (50 ml×2) and brine (50 ml), and then dried over MgSO₄. Thefilterate was concentrated in vacuo to yield the title compound (2.84 g,87%).

¹H NMR (300 MHz, CDCl₃): δ 8.43 (s, 1H), 7.99 (d, 1H, J=8.1 Hz), 7.69(d, 1H, J=7.8 Hz), 3.39 (s, 6H)

Step 2: Synthesis of2-amino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide

N-Methoxy-N-methyl-2-nitro-4-trifluoromethyl-benzamide (2.54 g, 9.12mmol) was reacted with Pd/C (441 mg) under hydrogen atmosphere asdescribed above to yield title compound.

¹H NMR (300 MHz, CDCl₃): δ 7.47 (d, 1H, J=7.8 Hz), 6.93 (s, 1H), 6.91(d, 1H, J=7.8 Hz), 3.56 (s, 3H), 3.36 (s, 3H).

Step 3: Synthesis of2-ethylamino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide

2-Amino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (482 mg, 1.94mmol) was reacted with acetaldehyde (0.12 ml, 2.14 mmol) and sodiumacetoxyborohydride (892 mg, 4.20 mmol) in CH₂Cl₂ at room temperature asdescribed above to yield title compound (95 mg, 17%).

¹H NMR (300 MHz, CDCl₃): δ 7.44 (d, 1H, J=8.1 Hz), 6.86 (s, 1H), 6.84(d, 1H, J=7.8 Hz), 3.57 (s, 3H), 3.35 (s, 3H), 3.18 (q, 2H, J=6.9 Hz),1.28 (t, 3H, J=7.2 Hz).

Step 4: Synthesis of 2-ethylamino-4-trifluoromethyl-benzaldehyde

2-Ethylamino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (95 mg,0.343 mmol) was reacted with LAH in THF at −40° C. for 1.5 hrs asdescribed above to yield title compound (22 mg, 29%) after columnchromatography (hexane/ethylacetate=20/1).

¹H NMR (300 MHz, CDCl₃): δ 9.88 (s, 1H), 8.35 (br, 1H), 7.57 (d, 1H,J=7.8 Hz), 6.88 (s, 1H), 6.87 (d, 1H, J=7.8 Hz), 3.30 (q, 2H, J=6.9 Hz),1.35 (t, 3H, J=7.2 Hz).

Step 5: Synthesis of 3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylicacid

2-Ethylamino-4-trifluoromethyl-benzaldehyde (22 mg) was reacted withmethyl (triphenylphosphoranylidene)acetate (49 mg, 0.14 mmol) at 110° C.overnight as described above to yield3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester.3-(2-Ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester wasreacted with 1N LiOH (5 ml) as described above to yield the titlecompound (20.2 mg)

¹H NMR (300 MHz, CDCl₃): δ 7.87 (d, 1H, J=15.6 Hz), 7.45 (d, 1H, J=8.1Hz), 6.94 (d, 1H, J=7.8 Hz), 6.86 (s, 1H), 6.39 (d, 1H, J=15.6 Hz), 3.27(q, 2H, J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).

Step 6: Synthesis of(R)—N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(31 mg, 0.108 mmol) was reacted with3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid (20 mg, 0.078mmol), NMM (0.1 ml) and DMTMM (27 mg) to give the title compound (11 mg,29%).

¹H NMR (300 MHz, CDCl₃): δ 7.79 (d, 1H, J=15 Hz), 7.37 (d, 1H, J=7.8Hz), 6.96 (d, 1H, J=8.1 Hz), 6.62 (s, 1H), 6.48 (br, 1H), 6.33 (d, 1H,J=15.3 Hz), 5.52 (d, 1H), 5.18 (t, 1H), 3.16 (s, 3H), 3.14 (t, 2H, J=7.2Hz), 1.70 (m, 3H), 1.35 (t, 3H, J=7.5 Hz)

ESI [M−H]⁻: 490

Example 11N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt(25 mg) was reacted with3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid (24 mg, 0.086mmol), NMM (0.1 ml) and DMTMM (27 mg) at room temperature overnight toyield the title compound (21 mg, 50%).

¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, 1H, J=15.3 Hz), 7.36 (d, 1H, J=8.1Hz), 7.14 (m, 1H), 7.11 (m, 1H), 6.88 (m, 1H), 6.80 (d, 1H, J=15.3 Hz),6.15 (t, 1H), 4.56 (d, 2H, J=6.0 Hz), 3.13 (t, 2H, J=7.2 Hz), 3.02 (s,3H), 2.24 (s, 3H), 1.70 (m, 2H), 0.96 (t, 3H, J=7.5 Hz)

ESI [M−H]⁻: 486

Example 12N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-vinyl-phenyl)-methanesulfonamide, HCl salt(36 mg, 0.15 mmol) was reacted with3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid (28 mg, 0.10mmol), NMM (0.1 ml) and DMTMM (35 mg) at room temperature overnight toyield the title compound (17 mg, 34%) after column chromatography.

¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, 1H, J=15.3 Hz), 7.38 (m, 1H), 7.22(m, 1H), 7.15 (m, 1H), 7.11 (m, 1H), 6.90 (d, 1H, J=7.2 Hz), 6.83 (s,1H), 6.34 (d, 1H, J=15.0 Hz), 5.95 (br, 2H), 5.81 (d, 1H, J=17.4 Hz),5.46 (d, 1H, J=10.8 Hz), 4.58 (d, 2H, J=6.0 Hz), 3.16 (t, 2H, J=6.0 Hz),3.08 (s, 3H), 1.69 (m, 2H), 1.03 (t, 3H, J=7.5 Hz)

ESI [M−H]⁻: 498

Example 13N-(3-Cyano-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-cyano-phenyl)-methanesulfonamide, HCl salt(26 mg, 0.092 mmol) was reacted with3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylic acid (20 mg, 0.073mmol), NMM (0.1 ml) and DMTMM (28 mg) at room temperature overnight toyield the title compound (8 mg, 22%) after column chromatography.

¹H NMR (300 MHz, CDCl₃): δ 7.82 (d, 1H, J=4.7 Hz), 7.45 (m, 1H), 7.40(m, 1H), 7.37 (m, 1H), 7.21 (s, 1H), 7.11 (m, 1H), 6.90 (d, 1H, J=7.8Hz), 6.84 (s, 1H), 6.36 (d, 1H, J=15.0 Hz), 6.10 (br, 1H), 4.58 (d, 2H,J=6.3 Hz), 3.32 (s, 3H), 3.16 (t, 2H, J=6.0 Hz), 1.69 (m, 2H), 1.03 (t,3H, J=7.5 Hz)

ESI [M−H]⁻: 497

Example 14N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt(53 mg, 0.19 mmol) was reacted with3-(2-propoxy-4-trifluoromethyl-phenyl)-acrylic acid (49 mg, 0.18 mmol),NMM (0.1 ml) and DMTMM (60 mg) at room temperature overnight to yieldthe title compound (63 mg, 70%) after column chromatography(Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=7.8Hz), 7.30 (s, 1H), 7.20 (m 1H), 7.11 (d, 1H, J=7.5 Hz), 6.97 (s, 1H),6.61 (d, 1H, J=15.9 Hz), 6.41 (br, 1H), 6.03 (br, 1H), 4.54 (d, 1H,J=6.3 Hz), 4.03 (t, 2H, J=6.6 Hz), 3.48 (s, 1H), 3.26 (s, 3H), 1.85 (m,2H), 1.06 (t, 3H, J=7.5 Hz)

Example 153-(2-Ethoxy-4-trifluoromethyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-5-trifluoromethyl-benzyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-trifluoromethyl-phenyl)-methanesulfonamide,HCl salt (61 mg, 0.19 mmol) was reacted with3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid (45 mg, 0.17 mmol),NMM (0.1 ml) and DMTMM (64 mg, 0.22 mmol) at room temperature to yieldthe title compound (63 mg, 0.12 mmol, 69%) after column chromatography(Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.95 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=7.5Hz), 7.40 (m, 1H), 7.19 (d, 1H, J=8.1 Hz), 7.10 (s, 1H), 6.63 (d, 1H,J=15.6 Hz), 6.22 (br, 1H), 4.60 (d, 2H, J=6.0 Hz), 4.12 (q, 2H, J=7.2Hz), 3.28 (s, 3H), 1.50 (t, 3H, J=7.2 Hz).

Example 16(R)-3-(2,6-Dibutyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

(R)—N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (43 mg, 0.15 mmol) was reacted with3-(2,6-dibutyl-4-trifluoromethyl-phenyl)-acrylic acid (50 mg, 0.15 mmol)to give the title compound (30 mg, 35%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, 1H, J=15.9 Hz), 7.29 (s, 1H), 7.26(s, 2H), 7.05 (m, 2H), 6.02 (s, 1H), 5.95 (d, 1H, J=15.9 Hz), 5.74 (s,1H), 5.34 (s, 1H), 5.21 (m, 1H), 3.22 (s, 3H), 2.63 (m, 4H), 1.32 (m,11H), 0.91 (m, 6H).

ESI [M+H]+:

Example 17(R)-3-(2,6-Diethyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

(R)—N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (38 mg, 0.13 mmol) was reacted with3-(2,6-diethyl-4-trifluoromethyl-phenyl)-acrylic acid (36 mg, 0.13 mmol)to give the title compound (20 mg, 30%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, CDCl₃): δ 7.84 (d, 1H, J=16.5 Hz), 7.29 (s, 1H), 7.30(s, 2H), 7.01 (m, 2H), 6.06 (s, 1H), 6.02 (d, 1H, J=16.2 Hz), 5.72 (s,1H), 5.30 (m, 1H), 5.24 (m, 1H), 3.19 (s, 3H), 2.69 (m, 4H), 1.24 (m,9H).

ESI [M−H]⁻: 503

Example 18N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-3,5-difluoro-phenyl)-methanesulfonamide, HCl salt (42mg, 0.154 mmol) was reacted with3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid (40 mg, 0.154mmol) to give the title compound (36 mg, 49%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, 1H, J=15 Hz), 7.38 (m, 2H), 6.95 (m,2H), 6.84 (s, 1H), 6.35 (d, 1H, J=15.6 Hz), 5.99 (s, 1H), 4.55 (d, 2H,J=6 Hz), 3.26 (m, 2H), 3.22 (s, 3H), 1.33 (m, 3H).

ESI [M−H]⁻: 476

Example 193-(2-Ethylamino-4-trifluoromethyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-5-methyl-benzyl)-acrylamide

N-(4-aminomethyl-3-fluoro-5-methyl-phenyl)-methanesulfonamide, HCl salt(28 mg, 0.104 mmol) was reacted with3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid (27 mg, 0.104mmol) to give the title compound (29 mg, 59%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, DMSO-d6): δ 8.59 (bs, 1H), 7.67 (d, 1H, J=15.6 Hz),7.47 (m, 2H), 6.88 (m, 1H), 6.57 (d, 1H, J=15.6 Hz), 6.04 (s, 1H), 4.40(d, 2H, J=5.4 Hz), 3.15 (m, 2H), 2.96 (s, 3H), 2.20 (s, 3H), 1.18 (m,3H).

ESI [M+H]⁺:

Example 20N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-3,5-difluoro-phenyl)-methanesulfonamide, HCl salt (14mg, 0.051 mmol) was reacted with3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid (14 mg, 0.051mmol) to give the title compound (11 mg, 40%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.70 (d, 1H, J=7.8 Hz), 7.69(m, 2H), 7.24 (m, 4H), 6.78 (d, 1H, J=15.9 Hz), 4.85 (m, 1H), 4.52 (d,2H, J=6.0 Hz), 3.02 (s, 3H), 1.31 (m, 6H).

ESI [M−H]⁻: 491

Example 21N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis of4,4-dimethyl-2-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazole

To an ice-cold solution of 2-amino-2-methyl-1-propanol (21.4 g, 240mmol) and triethylamine (16.8 mL, 120 mmol) in THF was added dropwise4-trifluoromethyl benzyl chloride (25.0 g, 120 mmol). After theaddition, the reaction mixture was stirred at 0° C. for 30 mins and thenstirred at ambient temperature for 8 hrs. The precipitate was removed byfiltration and the filtrate was concentrated by evaporating the solventunder reduced pressure. The resulting residue was treated dropwise withthionyl chloride with vigorous stirring at 0° C. After completeaddition, the reaction mixture was further stirred at ambienttemperature for 1 hr. Ether was poured into the reaction mixture and theprecipitate was collected by filtration. The precipitate was dissolvedin water and the aqueous solution was hydrolyzed with 10% (w/v) NaOH.The aqueous phase was extracted three times with ether, and the combinedorganic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (Hex/EtOAc=5/1) to yield the title compound (25.4g, 87%).

¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, 2H, J=7.8 Hz), 7.66 (d, 2H, J=7.8Hz), 4.14 (s, 2H), 1.39 (s, 6H).

Step 2: Synthesis ofN-methoxy-N-methyl-2-propyl-4-trifluoromethyl-benzamide

A solution of4,4-dimethyl-2-(4-trifluoromethyl-phenyl)-4,5-dihydro-oxazole (2.43 g,10.0 mmol) in THF was cooled to −78° C. under argon, and n-BuLi (2.5M inhexane, 4.0 mL, 10.0 mmol) was added dropwise to the solution. Theresulting dark brown solution was stirred for 2 hrs at −60° C. and thencooled again to −78° C., to which was added propyl iodide (1.88 mL, 19.0mmol). The reaction mixture was allowed to warm up to room temperature,and then stirred overnight. The reaction was quenched by adding waterand the aqueous phase was extracted three times with EtOAc. The combinedorganic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated under reduced pressure to give dark brown residue.

A mixture of the crude residue obtained above and 6N HCl (5.0 mL) washeated at reflux for 8 hrs. After cooling to ambient temperature, waterwas added to the reaction mixture and the aqueous layer was extractedthree times with EtOAc. The combined organic layer was washed withwater, brine, dried over anhydrous MgSO₄, and concentrated under reducedpressure. The resulting residue dissolved in THF was treated with 1NLiOH, and the resulting mixture was stirred 18 hrs at ambienttemperature and then 18 hrs at 70° C. After cooling, the reactionmixture was acidified with 2N HCl and then extracted three times withchloroform. The combined organic layer was washed with brine, dried overanhydrous MgSO₄, and concentrated under reduced pressure to give crudebenzoic acid product.

The resulting crude acid was dissolved in dichloromethane, to which wereadded successively N,O-dimethylhydroxylamine, HCl (630 mg, 6.46 mmol),NMM (0.71 mL, 6.46 mmol), and EDC (990 mg, 7.75 mmol). The resultingmixture was stirred overnight at ambient temperature and then quenchedby adding water. The aqueous layer was extracted three times with EtOAc,and the combined organic layer was washed with brine, dried overanhydrous MgSO₄, and concentrated under reduced pressure. The cruderesidue was purified by column chromatography (Hex/EtOAc=2/1) to yieldthe title compound (230 mg, 8%).

¹H NMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.36(d, 1H, J=7.8 Hz), 3.43 (bs, 3H), 3.36 (bs, 3H), 2.65 (t, 2H, J=7.8 Hz),1.67 (m, 2H), 0.97 (t, 3H, J=7.2 Hz).

Step 3: Synthesis of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acidmethyl ester

To a solution of N-methoxy-N-methyl-2-propyl-4-trifluoromethyl-benzamide(230 mg, 0.84 mmol) in THF (15 mL) was added dropwise 1.0M LiAlH₄ (0.42mL, 0.42 mmol) at −78° C. The mixture was warmed up to −20° C. andstirred for 30 mins An aqueous solution of sodium potassium tartrate(10% w/v) was added to the reaction mixture and the resulting mixturewas vigorously stirred for 30 mins, to which was added Et₂O. Afterseparation of two phases, the aqueous layer was extracted three timeswith ether and the combined organic layer was washed with brine, driedover anhydrous MgSO₄, filtered and concentrated under reduced pressure.The product was vacuum dried to yield the2-propyl-4-trifluoromethyl-benzaldehyde.

To a solution of the aldehyde obtained above in toluene was added methyl(triphenylphosphoranylidene)acetate (285 mg, 0.85 mmol), and theresulting mixture was heated at 80° C. for 3 hrs. The reaction mixturewas diluted with EtOAc, and washed with water and brine. The organiclayer was dried over anhydrous MgSO₄ and concentrated under reducedpressure. The resulting residue was purified by column chromatography(Hex/EtOAc=4/1) to give the title compound (220 mg, 96%).

¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, 1H, J=15.9 Hz), 7.63 (d, 1H, J=8.4Hz), 7.46 (d, 1H, J=8.4 Hz), 7.45 (s, 1H), 6.42 (d, 1H, J=15.9 Hz), 3.83(s, 3H), 2.77 (t, 2H, J=7.5 Hz), 1.63 (m, 2H), 0.98 (t, 3H, J=7.5 Hz).

Step 4: Synthesis of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid

To a suspension of 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acidmethyl ester (220 mg, 0.81 mmol) in THF (3 mL) was added a solution of1N—LiOH (6 ml), and the mixture was stirred for 3 hours at roomtemperature. The reaction mixture was diluted with H₂O, which was washedthree times with EtOAc, acidified with 1N HCl to pH 1-2. The resultingsolution was extracted three times with methylene chloride and thendried over anhydrous MgSO₄ and concentrated in vacuo to give the titlecompound (155 mg, 74%).

¹H NMR (300 MHz, CDCl₃): δ 8.09 (d, 1H, J=15.9 Hz), 7.67 (d, 1H, J=7.8Hz), 7.49 (d, 1H, J=7.8 Hz), 7.47 (s, 1H), 6.44 (d, 1H, J=15.9 Hz), 2.79(t, 2H, J=7.5 Hz), 1.64 (m, 2H), 0.99 (t, 3H, J=7.5 Hz).

Step 5: Synthesis of(R)—N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

To a suspension of(R)—N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (67 mg, 0.23 mmol) in THF (5 mL) was added N-methylmorpholine (51μl, 0.46 mmol). The mixture was stirred for 5 minutes, to which wereadded 3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (60 mg, 0.23mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholiniumchloride hydrate (DMTMM, 76 mg, 0.28 mmol). The mixture was stirredovernight at room temperature and was concentrated under reducedpressure. The residue was diluted with EtOAc and water. The organiclayer was washed with saturated sodium bicarbonate, 1N HCl and brine,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by recrystallizationfrom n-Hex/EtOAc to give title compound (83 mg, 74%).

¹H NMR (300 MHz, CD₃OD): δ 7.99 (d, 1H, J=15.6 Hz), 7.86 (d, 1H, J=8.7Hz), 7.60 (bs, 2H), 7.18 (d, 2H, J=8.7 Hz), 6.75 (d, 1H, J=15.6 Hz),5.20 (m, 1H), 3.17 (s, 3H), 2.90 (t, 2H, J=7.8 Hz), 1.70 (m, 2H), 1.61(d, 3H, J=7.2 Hz), 1.06 (t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 489

Example 22N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2,5-difluoro-phenyl)-methanesulfonamide, HCl salt (33mg, 0.12 mmol) was reacted with3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (25 mg, 0.097 mmol)to give the title compound (30 mg, 65%) after purification by columnchromatography (gradient 12% to 100% EtOAc in Hex).

¹H NMR (300 MHz, CD₃OD): δ 8.05 (d, 1H, J=15.6 Hz), 7.87 (d, 1H, J=8.7Hz), 7.62 (bs, 2H), 7.16 (d, 2H, J=8.7 Hz), 6.76 (d, 1H, J=15.6 Hz),4.61 (s, 2H), 3.18 (s, 3H), 2.93 (t, 2H, J=7.8 Hz), 1.71 (m, 2H), 1.09(t, 3H, J=7.5 Hz).

ESI [M+H]⁺:

Example 23N-(3-Fluoro-4-methanesulfonylamino-5-methyl-benzyl)-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2-fluoro-6-methyl-phenyl)-methanesulfonamide, HCl salt(32 mg, 0.12 mmol) was reacted with3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (25 mg, 0.097 mmol)to give the title compound (30 mg, 63%) after purification by columnchromatography (gradient 12% to 100% EtOAc in Hex).

¹H NMR (300 MHz, CD₃OD): δ 8.05 (d, 1H, J=15.6 Hz), 7.85 (d, 1H, J=8.1Hz), 7.60 (m, 2H), 7.30 (m, 2H), 6.74 (d, 1H, J=15.6 Hz), 4.64 (s, 2H),3.08 (s, 3H), 2.92 (t, 2H, J=7.5 Hz), 2.38 (d, 3H, J=2.1 Hz), 1.72 (m,2H), 1.08 (t, 3H, J=7.5 Hz).

ESI [M+H]⁺:

Example 24(R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

3-(2-Butyl-4-trifluoromethyl-phenyl)-acrylic acid was obtained by theprocedure in example 21.

(R)—N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (38 mg, 0.13 mmol) was reacted with3-(2-butyl-4-trifluoromethyl-phenyl)-acrylic acid (30 mg, 0.11 mmol) togive the title compound (29 mg, 43%) after purification by columnchromatography (gradient 12% to 100% EtOAc in Hex).

¹H NMR (300 MHz, CD₃OD): δ 7.90 (d, 1H, J=15.6 Hz), 7.76 (d, 1H, J=8.7Hz), 7.51 (bs, 2H), 7.08 (d, 2H, J=8.7 Hz), 6.65 (d, 1H, J=15.6 Hz),5.10 (m, 1H), 3.07 (s, 3H), 2.82 (t, 2H, J=7.8 Hz), 1.55 (m, 2H), 1.51(d, 3H, J=7.2 Hz), 1.40 (m, 2H), 0.94 (t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 503

Example 25(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-propyl]-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-[4-(1-Amino-propyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (15 mg, 0.050 mmol) was reacted with3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (8 mg, 0.03 mmol) togive the title compound (15 mg, 97%) after purification by columnchromatography (gradient 12% to 100% EtOAc in Hex).

¹H NMR (300 MHz, DMSO-d6): δ 8.65 (d, 1H, J=8.1 Hz), 7.69 (m, 4H), 7.11(d, 2H, J=8.4 Hz), 6.75 (d, 1H, J=15.6 Hz), 4.82 (m, 1H), 2.98 (s, 3H),2.75 (t, 2H, J=7.8 Hz), 1.71 (m, 2H), 1.52 (m, 2H), 1.23 (m, 2H), 0.89(m, 6H).

ESI [M+H]⁺:

Example 26(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis of 2-isopropoxy-4-trifluoromethyl-benzoic acidisopropyl ester

A mixture of 2-hydroxy-4-trifluoromethyl-benzoic acid (500 mg, 2.42mmol) in DMF (5 mL) was added potassium carbonate (837 mg, 6.06 mmol)and 2-bromopropane (906 mg, 5.33 mmol). The resulting mixture wasstirred for 48 hours at 110° C. The reaction mixture was diluted withEtOAc, which was washed with 1N HCl, water, and brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The crude residue was purified by chromatography(Hex/EtOAc=5/1) to give the title compound (200 mg, 28%).

¹H NMR (300 MHz, CDCl₃): δ 7.73 (d, 1H, J=8.1 Hz), 7.19 (d, 1H, J=8.4Hz), 7.15 (s, 1H), 5.31-5.29 (m, 1H), 4.68-4.60 (m, 1H), 1.40 (d, 6H,J=6.9 Hz), 1.36 (d, 6H, J=6.6 Hz).

Step 2: Synthesis of2-isopropoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide

To a suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid isopropylester (35 mg, 0.12 mmol) in THF (1 ml) was added a solution of 0.5N—LiOH (2 eq), and the resulting mixture was stirred for 2 hours at roomtemperature. The reaction mixture was acidified with 1N HCl, and thenextracted with EtOAc. The combined organic layer was washed with waterand brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was vacuumdried to yield the 2-isopropoxy-4-trifluoromethyl-benzoic acid. To anice-cold suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid andN,O-dimethylhydroxylamine hydrochloride (13 mg, 0.132 mmol) in CH₂Cl₂ (1mL) was added N-methylmorpholine (0.015 ml, 0.132 mmol), and theresulting mixture was stirred for 5 minutes, to which were addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26 mg,0.132 mmol). The resulting mixture was stirred for 2 hours at roomtemperature, and then diluted with EtOAc. The organic layer was washedwith 1N HCl, water, and brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The crude residue waspurified by chromatography (Hex/EtOAc=3/1) to give the title compound(28 mg, 80%).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.18 (m, 2H), 7.11 (s, 1H), 4.66-4.60(m, 1H), 3.46 (s, 3H), 3.35 (s, 3H), 1.34 (d, 6H, J=6.0 Hz).

Step 3: Synthesis of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylicacid methyl ester

To a suspension of2-isopropoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (28 mg,0.096 mmol) in THF (1.5 mL) was added dropwise 1.0M LiAlH₄ (0.048 ml,0.5 eq) at −60° C. The mixture was slowly warmed up to −20° C. until thereaction was completed. The reaction was slowly quenched with sat'dKHSO₄ (1 mL) and then diluted with water (1 mL). The reaction mixturewas extracted with ether and the combined organic layer was dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresulting compound was vacuum dried to yield the2-isopropoxy-4-trifluoromethyl-benzaldehyde. To the aldehyde preparedabove was added toluene (1 mL) followed by portionwise addition ofmethyl (triphenylphosphoranylidene)acetate (32 mg, 0.105 mmol)(exothermic). Toluene (1 mL) was added to the reaction mixture, and theresulting mixture was heated at 80° C. for 3 hours. The reaction mixturewas cooled to room temperature, and then was directly loaded to a shortsilica-gel column and eluted with the solvent (Hex/EtOAc=20/1) to givethe title compound (20 mg, 72%).

¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, 1H, J=16.2 Hz), 7.58 (d, 1H, J=8.1Hz), 7.17 (d, 1H, J=7.8 Hz), 7.11 (s, 1H), 6.57 (d, 1H, J=16.2 Hz),4.71-4.63 (m, 1H), 3.81 (s, 3H), 1.41 (d, 6H, J=6.3 Hz).

Step 4: Synthesis ofN-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylamide

To a suspension of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylicacid methyl ester (15 mg, 0.052 mmol) in THF (1 ml) was added a solutionof 0.5 N—LiOH (0.2 ml), and the resulting mixture was stirred for 3hours at room temperature. The reaction mixture was acidified with 1NHCl to pH 1-2. The mixture solution was extracted three times withmethylene chloride, and the combined organic layer was dried overanhydrous Na₂SO₄ and concentrated in vacuo to give3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid (14 mg, 98%). Toa suspension of 3-(2-isopropoxy-4-trifluoromethyl-phenyl)-acrylic acid(14 mg, 0.051 mmol) andN-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt(17.2 mg, 0.060 mmol) in DMF (2 mL) was added N-methylmorpholine (0.007ml, 0.060 mmol). The mixture was stirred for 5 minutes, to which wereadded N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26mg, 0.132 mmol). The mixture was stirred for 12 hours at roomtemperature, and then diluted with EtOAc (4 mL). The organic layer waswashed with 1N HCl, water, and brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The cruderesidue was purified by chromatography (Hex/EtOAc=1/1) to give the titlecompound (24 mg, 79%).

¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=7.8Hz), 7.16 (d, 1H, J=8.1 Hz), 7.10 (s, 1H), 7.01 (d, 1H, J=8.4 Hz), 6.54(d, 1H, J=15.6 Hz), 5.82 (d, 1H, J=6.9 Hz), 5.19 (t, 1H, J=6.9 Hz),4.67-4.63 (m, 1H), 3.20 (s, 3H), 1.56 (d, 6H, J=6.3 Hz). 1.40 (d, 3H,J=5.4 Hz).

ESI [M−H]⁻: 505

Example 27(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2-propoxy-phenyl)-acrylamide

Step 1: Synthesis of 3-(4-fluoro-2-hydroxy-phenyl)-acrylic acid methylester

2-Hydroxy-4-fluoro-benzaldehyde (306 mg, 1.99 mmol) was reacted withmethyl (triphenylphosphoranylidene)acetate (681 g, 2.044 mmol) at 110°C. overnight as described above to yield title compound (334 mg, 85%).

¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, 1H, J=15.9 Hz), 7.45 (m, 1H), 6.65(m, 1H), 6.59 (m, 1H), 6.56 (s, 1H), 6.53 (d, 1H, J=16.2 Hz), 5.27 (br,1H), 3.82 (s, 3H).

Step 2: Synthesis of 3-(4-fluoro-2-propoxy-phenyl)-acrylic acid methylester

3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (110.5 mg) wasreacted with K₂CO₃ (111 mg) and propane iodide (0.1 ml) at 80° C.overnight as described above to yield title compound (134 mg, 100%)

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, 1H, J=15.9 Hz), 7.45 (t, 1H, J=7.5Hz), 6.65 (m, 1H), 6.59 (m, 1H), 6.49 (d, 1H, J=15.9 Hz), 3.96 (t, 2H,J=6.6 Hz), 3.78 (s, 3H), 1.89 (m, 2H), 1.07 (t, 3H, J=7.5 Hz).

Step 3: Synthesis of 3-(4-fluoro-2-propoxy-phenyl)-acrylic acid

3-(4-Fluoro-2-propoxy-phenyl)-acrylic acid methyl ester (134 mg, 0.563mmol) was reacted with aqueous 1N LiOH (5 ml) as described above toyield title compound (117 mg, 92%).

¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, 1H, J=16.5 Hz), 7.49 (t, 1H, J=8.4Hz), 6.67 (m, 2H) 6.50 (d, 1H, J=15.9 Hz), 3.98 (t, 2H, J=6.6 Hz), 1.91(m, 2H), 1.09 (t, 3H, J=7.2 Hz).

Step 4: Synthesis of(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2-propoxy-phenyl)-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(85 mg, 0.29 mmol) was reacted with3-(4-fluoro-2-propoxy-phenyl)-acrylic acid (65 mg, 0.29 mmol), NMM (0.15ml) and DMTMM (98 mg) at room temperature overnight to yield the titlecompound (77 mg, 58%) after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.84 (d, 1H, J=15.6 Hz), 7.43 (t, 1H, J=6.9Hz), 6.98 (d, 1H, J=8.7 Hz), 6.63 (m, 2H), 6.47 (d, 1H, J=15.6 Hz), 5.87(br, 1H), 5.18 (m, 1H), 4.11 (t, 2H, J=6.9 Hz), 3.19 (s, 3H), 1.87 (m,2H), 1.09 (t, 3H, J=7.5 Hz)

Example 28N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(4-fluoro-2-propoxy-phenyl)-acrylamide

N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (66mg, 0.24 mmol) was reacted with 3-(4-fluoro-2-propoxy-phenyl)-acrylicacid (51 mg, 0.23 mmol), NMM (0.15 ml) and DMTMM (78 mg) at roomtemperature overnight to yield the title compound (52 mg, 0.12 mmol,53%) after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, 1H, J=15.9 Hz), 7.44 (t, 1H, J=6.6Hz), 6.99 (d, 1H, J=8.1 Hz), 6.65 (m, 2H), 6.52 (d, 1H, J=15.6 Hz), 5.89(br, 1H), 4.55 (d, 2H, J=6.0 Hz), 3.98 (t, 2H, J=6.6 Hz), 3.21 (s, 3H),1.90 (m, 2H), 1.08 (t, 3H, J=7.5 Hz).

Example 29(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)ethyl]-3-(4-fluoro-2-propylaminophenyl)-acrylamide

Step 1. Synthesis of N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide

To a solution of 4-fluoro-2-nitrobenzoic acid (1 g, 5.4 mmol),N,O-dimethylhydroxylamine hydrochloride (0.58 g, 5.95 mmol) andN-methylmorpholine (0.65 mL, 5.91 mmol) in dichloromethane (20 mL) wasadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.14g, 5.95 mmol). The mixture was stirred for 80 minutes at roomtemperature. The mixture was concentrated under reduced pressure andthen diluted with EtOAc and water. The organic layer was washed with 3 NHCl, saturated aqueous NaHCO₃ solution and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure togive N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide (1.15 g, 95%).

¹H NMR (300 MHz, CDCl₃): δ 7.89˜7.85 (m, 1H), 7.58˜7.54 (m, 1H),7.47˜7.41 (m, 1H), 3.37 (s, 3H), 3.36 (s, 3H).

Step 2. Synthesis of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide

A mixture of N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide (1.15 g, 5.04mmol) and 5% palladium charcoal (190 mg) in EtOH (30 mL) was shakenovernight under hydrogen atmosphere (3 atm). The mixture was filteredand concentrated under reduced pressure to giveN-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.9 g, 90%).

¹H NMR (300 MHz, CDCl₃): δ 7.44˜7.39 (m, 1H), 6.40˜6.30 (m, 2H), 4.90(bs, 2 H), 3.57 (s, 3H), 3.34 (s, 3H).

Step 3. Synthesis of N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide

To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.27 g,1.36 mmol), propionaldehyde (0.15 mL, 2.08 mmol), and AcOH (0.12 mL, 2.1mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride(576 mg, 2.72 mmol) at 5° C. The mixture was stirred for 90 minutes atthe same temperature and then 40 minutes at room temperature. Thereaction was quenched by adding water. The organic layer was washed withsaturated aqueous NaHCO₃ solution and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure togive N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide quantitatively.

¹H NMR (300 MHz, CDCl₃): δ 7.40 (t, 1H, J=7.2 Hz), 6.34˜6.25 (m, 2H),3.58 (s, 3 H), 3.33 (s, 3H), 3.03 (t, 2H, J=6.9 Hz), 1.72˜1.59 (m, 2H),1.00 (t, 3H, J=7.2 Hz).

Step 4. Synthesis of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acidmethyl ester

To a solution of N-methoxy-N-methyl-4-fluoro-2-propylamino-benzamide(0.33 g, 1.37 mmol) in THF (4 mL) was added dropwise LiAlH₄ (1 M in THF,0.7 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. andthen quenched by adding saturated aqueous KHSO₄ solution. The mixturewas diluted with EtOAc, washed with 3 N HCl, and brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was reacted with methyl(triphenylphosphoranylidene)acetate (0.5 g, 1.5 mmol) in toluene (4 mL)overnight at 100° C. The mixture was washed with water, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give the title compound (0.23 g, 69%) after purification bycolumn chromatography (EtOAc:hexane=1:10).

¹H NMR (300 MHz, CDCl₃): δ 7.72 (d, 1H, J=15.6 Hz), 7.34˜7.29 (m, 1H),6.41˜6.29 (m, 2H), 6.27 (d, 1H, J=15.6 Hz), 4.16 (bs, 1H), 3.80 (s, 3H),3.12˜3.07 (m, 2

H), 1.76˜1.63 (m, 2H), 1.02 (t, 3H, J=7.2 Hz).

Step 5. Synthesis of (R)—N-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethyl]-3-(4-fluoro-2-propylamino-phenyl)-acrylamide

To a solution of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid methylester (0.23 g, 0.95 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 NLiOH (4 mL). The mixture was stirred for 2 hours at room temperature,concentrated under reduced pressure, and then acidified with 3 N HCl.The mixture was diluted with EtOAc, washed with water, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (0.17 g,79%) after purification by crystallization form EtOAc and hexane. To amixture of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (50 mg, 0.22mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethylaminehydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33mmol) in THF (5 mL) was added4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloridehydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight atroom temperature and then concentrated under reduced pressure. Theresidue was diluted with EtOAc and water, and the aqueous layer waswashed with 2 N HCl and brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure to give the titlecompound (35 mg, 34%) after purification by crystallization form EtOAcand hexane.

¹H NMR (300 MHz, CDCl₃): δ 7.78 (d, 1H, J=15 Hz), 7.32˜7.26 (m, 1H),6.93 (d, 2

H, J=8.4 Hz), 6.78 (s, 1H), 6.37˜6.29 (m, 2H), 6.22 (d, 1H, J=15 Hz),5.87 (d, 1H, J=6.9 Hz), 5.13 (t, 1H, J=6.9 Hz), 4.48 (bs, 1H), 3.18 (s,3H), 3.08 (t, 2H, J=6.9 Hz), 1.71˜1.58 (m, 2H), 1.49 (d, 3H, J=6.9 Hz),0.99 (t, 3H, J=7.2 Hz).

Example 30N-[1-(3,5-Difluoro-4-methanesulfonylaminobenzyl]-3-(4-fluoro-2-n-propylamino-phenyl)-acrylamide

To a mixture of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (50 mg,0.22 mmol), (3,5-difluoro-4-methanesulfonylamino)benzylaminehydrochloride (61 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33mmol) in THF (5 mL) was added4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloridehydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight atroom temperature and then concentrated under reduced pressure. Theresidue was diluted with EtOAc and water, and the aqueous layer waswashed with 2 N HCl and brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure to give the titlecompound (9 mg, 9%) after purification by column chromatography(EtOAc:hexane=1:1).

¹H NMR (300 MHz, CDCl₃): δ 7.60 (d, 1H, J=15 Hz), 7.32˜7.26 (m, 1H),6.96 (d, 2 H, J=8.1 Hz), 6.93˜6.32 (m, 2H), 6.14 (d, 1H, J=15 Hz), 6.13(br, 1H), 5.95 (br, 1 H), 4.53 (d, 2H, J=5.7 Hz), 4.25 (br, 1H), 3.21(s, 3H), 3.09 (m, 2H), 1.72˜1.65 (m, 2H), 1.01 (t, 3H, J=7.2 Hz).

Example 31(R)-3-(2-Butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

Step 1: Synthesis of 2-butoxy-4-trifluoromethyl-benzoic acid butyl ester

2-Hydroxy-4-trifluoromethyl-benzoic acid (755 mg) was reacted withbutylbromide (0.96 ml) and K₂CO₃ (1.15 g) in DMF solution as describedabove to yield title compound.

¹H NMR (300 MHz, CDCl₃): δ 8.01 (s, 1H), 7.801 (d, 1H, J=7.8 Hz), 7.19(m, 2H), 4.32 (t, 2H, J=6.6 Hz), 4.06 (t, 2H, J=6.3 Hz), 1.82 (m, 2H),1.75 (m, 2H), 0.98 (m, 6H)

Step 2: Synthesis of 2-butoxy-4-trifluoromethyl-benzoic acid2-Butoxy-4-trifluoromethyl-benzoic acid butyl ester was reacted with 1NLiOH (10 ml) as described above to yield title compound (687 mg)

¹H NMR (300 MHz, CDCl₃): δ 8.29 (d, 1H, J=8.4 Hz), 7.38 (d, 1H, J=8.1Hz), 4.31 (t, 2H, J=6.3 Hz), 1.94 (m, 2H), 1.53 (m, 2H), 1.02 (t, 3H,J=7.5 Hz)

Step 3: Synthesis of2-butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide

2-Butoxy-4-trifluoromethyl-benzoic acid (687 mg) was reacted withN,O-dimethylhydroxy amine (331 mg), NMM (0.65 ml) and DMTMM (911 mg) asdescribed above to yield the title compound (825 mg) after columnchromatography (Hex/EtOAc=7.5/1).

¹H NMR (300 MHz, CDCl₃): δ 7.36 (br, 1H), 7.22 (d, 1H, J=8.1 Hz), 7.11(s, 1H), 4.04 (t, 2H, J=6.3 Hz), 3.45 (s, 3H), 3.35 (s, 3H), 1.77 (m,2H), 1.46 (m, 2H), 0.99 (t, 3H, J=7.5 Hz)

Step 4: Synthesis of 2-butoxy-4-trifluoromethyl-benzaldehyde

2-Butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (825 mg) wasreacted with 1 M LAH (31 ml) at −50° C. for 1 hour as described above toyield title compound (423 mg) after column chromatography(Hex/EtOAc=20/1).

¹H NMR (300 MHz, CDCl₃): δ 10.53 (s, 1H), 7.92 (d, 1H, J=7.8 Hz), 7.27(d, 1H, J=8.7 Hz), 7.21 (s, 1H), 4.10 (t, 2H, J=6.3 Hz), 1.89 (m, 2H),1.57 (m, 2H), 1.01 (t, 3H, J=7.2 Hz)

Step 5: Synthesis of 3-(2-butoxy-4-trifluoromethyl-phenyl)-acrylic acidmethyl ester

2-Butoxy-4-trifluoromethyl-benzaldehyde (420 mg) was reacted with methyl(triphenylphosphoranylidene)acetate (679 mg) at 110° C. overnight asdescribed above to yield title compound (464 mg) after columnchromatography (Hex/EtOAc=20/1).

¹H NMR (300 MHz, CDCl₃): δ 7.91 (d, 1H, J=16.5 Hz), 7.53 (d, 1H, J=7.8Hz), 7.13 (m, 1H), 7.06 (s, 1H), 6.54 (d, 1H, J=16.2 Hz), 4.03 (t, 2H,J=6.6 Hz), 3.77 (s, 3H), 1.82 (m, 2H), 1.48 (m, 2H), 0.96 (t, 3H, J=7.5Hz)

Step 6: Synthesis of 3-(2-butoxy-4-trifluoromethyl-phenyl)-acrylic acid

3-(2-Butoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (464 mg)was reacted with 1N LiOH (10 ml) in THF and CH₃OH for 1 hr as describedabove to yield title compound

¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, 1H, J=16.2 Hz), 7.60 (d, 1H, J=8.1Hz), 7.20 (m, 1H), 7.12 (s, 1H), 6.62 (d, 1H, J=16.2 Hz), 4.09 (t, 2H,J=6.0 Hz), 1.85 (m, 2H), 1.56 (m, 2H), 1.04 (t, 3H, J=7.5 Hz)

Step 7: Synthesis of(R)-3-(2-butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(75 mg, 0.26 mmol) was reacted with3-(2-butoxy-4-trifluoromethyl-phenyl)-acrylic acid (63 mg, 0.230 mmol),NMM (0.15 ml) and DMTMM (75 mg) at room temperature overnight to yieldthe title compound (52 mg, 0.10 mmol, 43%) after column chromatography(Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, 1H, J=15.6 Hz), 7.55 (d, 1H, J=7.8Hz), 7.18 (d, 1H, J=8.1 Hz), 6.99 (d, 1H, J=6.6 Hz), 6.75 (d, 1H, J=8.4Hz), 6.52 (d, 1H, J=15.6 Hz), 5.89 (br, 1H), 5.18 (t, 1H), 4.10 (d, 2H,J=6.0 Hz), 3.19 (s, 3H), 1.87 (m, 2H), 1.52 (m, 2H), 0.99 (t, 3H, J=7.2Hz).

ESI [M−H]⁻: 519

Example 323-(2-Butoxy-4-trifluoromethyl-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)-acrylamide

N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (65mg, 0.24 mmol) was reacted with3-(2-butoxy-4-trifluoromethyl-phenyl)-acrylic acid (57 mg, 0.20 mmol),NMM (0.2 ml) and DMTMM (66 mg) to give the title compound (62 mg, 012mmol, 62%) after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=8.1Hz), 7.20 (d, 1H, J=7.2 Hz), 7.11 (s, 1H), 6.99 (d, 1H, J=8.1 Hz), 6.75(d, 1H, J=8.1 Hz), 6.52 (d, 1H, J=15.6 Hz), 6.05 (br, 1H), 4.55 (d, 2H,J=6.3 Hz), 4.10 (d, 2H, J=6.9 Hz), 3.20 (s, 3H), 1.88 (m, 2H), 1.57 (m,2H), 0.98 (t, 3H, J=7.2 Hz).

Example 33(R)-3-(2-Butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

Step 1: Synthesis of 3-(2-butoxy-4-fluoro-phenyl)-acrylic acid methylester

3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (106 mg) wasreacted with K₂CO₃ (125 mg) and butyl iodide (0.1 ml) at 80° C. for 3hrs as described above to yield title compound (121 mg).

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, 1H, J=16.2 Hz), 7.45 (m, 1H), 6.64(m, 2H), 6.47 (d, 1H, J=15.9 Hz), 4.00 (t, 2H, J=6.6 Hz), 3.79 (s, 3H),1.84 (m, 2H), 1.53 (m, 2H), 0.99 (t, 3H, J=7.2 Hz)

Step 2: Synthesis of 3-(2-butoxy-4-fluoro-phenyl)-acrylic acid

3-(2-Butoxy-4-fluoro-phenyl)-acrylic acid methyl ester (121 mg) wasreacted with 1N LiOH (5 ml) in THF and CH₃OH for 2 hrs as describedabove to yield title compound (116 mg).

¹H NMR (300 MHz, CDCl₃): δ 7.99 (d, 1H, J=16.2 Hz), 7.48 (m, 1H), 6.65(m, 2H), 6.49 (d, 1H, J=16.2 Hz), 4.02 (t, 2H, J=6.3 Hz), 1.86 (m, 2H),1.54 (m, 2H), 1.00 (t, 3H, J=7.2 Hz).

Step 3: Synthesis of(R)-3-(2-butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(75 mg, 0.26 mmol) was reacted with 3-(2-butoxy-4-fluoro-phenyl)-acrylicacid (60 mg, 0.25 mmol), NMM (0.15 ml) and DMTMM (82 mg) at roomtemperature overnight to yield the title compound (87 mg, 0.19 mmol,74%) after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.85 (d, 1H, J=15.9 Hz), 7.42 (m, 1H), 6.94(d, 2H, J=8.4 Hz), 6.62 (m, 2H), 6.47 (d, 1H, J=15.6 Hz), 6.23 (d, 1H,J=7.2 Hz), 5.13 (t, 1H), 4.11 (t, 2H, J=6.3 Hz), 3.17 (s, 3H), 1.81 (m,2H), 1.54 (m, 2H), 1.46 (d, 3H, J=6.6 Hz), 0.90 (t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 469

Example 343-(2-Butoxy-4-fluoro-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)-acrylamide

N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (73mg, 0.26 mmol) was reacted with 3-(4-fluoro-2-propoxy-phenyl)-acrylicacid (55 mg, 0.23 mmol), NMM (0.15 ml) and DMTMM (73 mg) at roomtemperature overnight to yield the title compound (85 mg, 0.19 mmol,81%) after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.89 (d, 1H, J=15.6 Hz), 7.45 (m, 1H), 6.94(d, 2H, J=8.4 Hz), 6.98 (m, 1H), 6.64 (m, 1H), 6.50 (d, 1H, J=15.6 Hz),6.07 (br, 1H), 4.55 (d, 2H, J=6.0 Hz), 4.13 (t, 2H, J=6.3 Hz), 3.20 (s,3H), 1.83 (m, 2H), 1.52 (m, 2H), 0.88 (t, 3H, J=7.2 Hz).

Example 35N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide, HCl salt(14 mg, 0.050 mmol) was reacted with3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (8 mg, 0.03 mmol) togive the title compound (12 mg, 80%) after purification by columnchromatography (gradient 12% to 100% EtOAc in Hex).

¹H NMR (300 MHz, DMSO-d⁶): δ 8.79 (t, 1H), 7.69 (m, 4H), 7.74 (m, 2H),7.60 (m, 2H), 7.26 (m, 2H), 6.72 (d, 1H, J=15.6 Hz), 4.45 (s, 1H), 4.38(d, 1H, J=5.4 Hz), 3.01 (s, 3H), 2.70 (t, 2H, J=7.5 Hz), 1.54 (m, 2H),1.23 (m, 2H), 0.91 (m, 3H).

ESI [M+H]⁺:

Example 36(R)-3-(2-Butyl-4-trifluoromethyl-phenyl)-N-[1-(3-fluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

(R)—N-[4-(1-Amino-ethyl)-2-fluoro-phenyl]-methanesulfonamide, HCl salt(20 mg, 0.074 mmol) was reacted with3-(2-butyl-4-trifluoromethyl-phenyl)-acrylic acid (8 mg, 0.03 mmol) togive the title compound (5 mg, 35%) after purification by columnchromatography (gradient 12% to 100% EtOAc in Hex).

¹H NMR (300 MHz, DMSO-d⁶): δ 8.66 (d, 1H, J=8.1 Hz), 7.66 (m, 3H), 7.51(bs, 2H), 7.31 (t, 1H, J=8.4 Hz), 7.17 (d, 1H, J=11.4 Hz), 7.09 (d, 1H,J=8.1 Hz), 6.70 (d, 1H, J=15.6 Hz), 5.00 (m, 1H), 2.91 (s, 3H), 2.78 (t,2H, J=7.8 Hz), 1.47 (m, 2H), 1.40 (d, 3H, J=7.2 Hz), 1.32 (m, 2H), 0.89(t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 485

Example 37N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-propyl]-3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylamide

To a suspension of 3-(2-ethoxy-4-trifluoromethyl-phenyl)-acrylic acid(39 mg, 0.151 mmol) andN-[4-(1-amino-propyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt(50 mg, 0.166 mmol) in DMF (2 mL) was added N-methylmorpholine (0.02 ml,0.018 mmol). The mixture was stirred for 5 minutes, to which were addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (33 mg,0.166 mmol). The mixture was stirred for 12 hours at room temperature,and then diluted with EtOAc (4 mL). The organic layer was washed with 1NHCl, water, and brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The crude residue was purifiedby chromatography (Hex/EtOAc=1/1) to give the title compound. (43 mg,51%).

¹H NMR (300 MHz, DMSO-d⁶): δ 9.50 (bs, 1H), 8.65 (d, 1H, J=7.8 Hz), 7.74(d, 1H, J=7.8 Hz), 7.67 (d, 1H, J=15.9 Hz), 7.33 (d, 1H, J=8.1 Hz), 7.31(s, 1H), 7.15 (d, 1H, J=8.7 Hz), 6.82 (d, 1H, J=15.9 Hz), 4.87-4.80 (m,1H), 4.19 (q, 2H, J=6.9 Hz), 3.04 (s, 3H), 1.75-1.70 (m, 2H), 1.39 (t,3H, J=6.9 Hz). 0.88 (t, 3H, J=6.9 Hz).

Example 383-(2-Butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-propyl]-acrylamide

N-[4-(1-Amino-propyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt(50 mg, 0.166 mmol) was reacted with3-(2-butoxy-4-trifluoromethyl-phenyl)-acrylic acid (43.5 mg, 0.151 mmol)to give the title compound (43 mg, 54%) after purification by columnchromatography.

¹H NMR (300 MHz, DMSO-d⁶): δ 9.47 (bs, 1H), 8.65 (d, 2H, J=8.1 Hz), 7.73(d, 1H, J=8.4 Hz), 7.68 (d, 1H, J=16.2 Hz), 7.33 (s, 1H), 7.15 (d, 2H,J=8.7 Hz), 6.80 (d, 1H, J=16.2 Hz), 4.82 (q, 1H, J=7.2 Hz), 4.12 (d, 2H,J=6.3 Hz), 3.04 (s, 3H), 1.83-1.67 (m, 4H), 1.51-1.41 (m, 2H), 0.96-0.86(m, 6H).

Example 39(R)-3-(2-sec-Butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

Step 1: Synthesis of2-sec-butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide

A mixture of 2-hydroxy-4-trifluoromethyl-benzoic acid (300 mg, 1.45mmol) in DMF was added potassium carbonate (442 mg, 3.20 mmol) followedby 2-iodobutane (589 mg, 3.2 mmol). The mixture was stirred for 48 hoursat 110° C. and then diluted with EtOAc. The organic layer was washedwith 1N HCl, water, and brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The crude residue wasdissolved in THF (2 ml) and then added a solution of 0.5 N—LiOH (2 eq).The mixture was stirred for 2 hours at room temperature and then dilutedwith EtOAc. The organic layer was washed with 1N HCl, water, and brine,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The crude residue and N,O-dimethylhydroxylaminehydrochloride (316 mg, 0.16 mmol) in CH₂Cl₂ (5 mL) was addedN-methylmorpholine (0.176 ml, 0.160 mmol). The mixture was stirred for 5minutes, to which were addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (316 mg,0.160 mmol). The mixture was stirred for 2 hours at room temperature andthen diluted with EtOAc. The organic layer was washed with 1N HCl,water, and brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The crude residue was purified bychromatography to give the title compound. (374 mg, 84%).

¹H NMR (300 MHz, CDCl₃): δ 7.23-7.19 (m, 2H), 7.09 (s, 1H), 4.40-4.37(m, 1H), 3.42 (s, 3H), 3.34 (s, 3H), 1.77-1.67 (m, 2H), 1.30 (d, 3H,J=3.0 Hz), 0.97 (t, 3H, J=7.2 Hz).

Step 2: Synthesis of 3-(2-sec-butoxy-4-trifluoromethyl-phenyl)-acrylicacid methyl ester

2-sec-Butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (130 mg,0.425 mmol) was processed with reduction and wittig reaction asdescribed above to give the title compound (100 mg, 61%) afterpurification by column chromatography.

¹H NMR (300 MHz, CDCl₃): 7.97 (d, 1H, J=16.2 Hz), 7.58 (d, 1H, J=7.8Hz), 7.17 (d, 1H, J=7.8 Hz), 7.09 (s, 1H), 6.57 (d, 1H, J=16.2 Hz),4.48-4.42 (m, 1H), 3.81 (s, 3H), 1.86-1.69 (m, 2H), 1.35 (d, 3H, J=6.0Hz), 1.01 (t, 3H, J=7.2 Hz).

Step 3: Synthesis of3-(2-sec-butoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt(17.7 mg, 0.062 mmol) was reacted with3-(2-sec-butoxy-4-trifluoromethyl-phenyl)-acrylic acid (16.2 mg, 0.056mmol) to give the title compound (15 mg, 52%) after purification bycolumn chromatography.

¹H NMR (300 MHz, CDCl₃): δ 7.93 (d, 1H, J=15.9 Hz), 7.56 (d, 1H, J=8.1Hz), 7.11 (d, 1H, J=8.1 Hz), 7.09 (s, 1H), 6.99 (d, 2H, J=8.1 Hz), 6.53(d, 1H, J=15.9 Hz), 5.96 (d, 1H, J=7.2 Hz), 5.23-5.14 (m, 1H), 4.43 (q,1H, J=6.0 Hz), 3.19 (s, 3H), 1.86-1.77 (m, 1H), 1.73-1.62 (m, 1H), 1.52(d, 3H, J=6.9 Hz), 1.33 (d, 3H, J=6.0 Hz), 0.99 (t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 519

Example 40(R)-3-(2-sec-Butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

Step 1: Synthesis of 3-(2-sec-butoxy-4-fluoro-phenyl)-acrylic acidmethyl ester

3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (120 mg) wasreacted with K₂CO₃ (165 mg) and 2-iodobutan (0.12 ml) at 100° C. for 3hrs as described above to yield title compound (105 mg)

¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, 1H, J=15.9 Hz), 7.45 (m, 1H), 6.63(m, 2H), 6.45 (d, 1H, J=15.9 Hz), 4.33 (m, 1H, J=6.0 Hz), 3.79 (s, 3H),1.82 (m, 1H), 1.71 (m, 1H), 1.33 (d, 2H, J=6.0 Hz), 0.99 (t, 3H, J=7.2Hz)

Step 2: Synthesis of 3-(2-sec-butoxy-4-fluoro-phenyl)-acrylic acid

3-(2-sec-Butoxy-4-fluoro-phenyl)-acrylic acid methyl ester (105 mg) wasreacted with 1N LiOH (5 ml) in THF and CH₃OH for 2 hrs as describedabove to yield title compound (82 mg)

¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, 1H, J=16.2 Hz), 7.50 (m, 1H), 6.62(m, 2H), 6.47 (d, 1H, J=16.2 Hz), 4.02 (m, 1H, J=6.0 Hz), 1.86 (m, 1H),1.73 (m, 1H), 1.34 (d, 3H), 1.00 (t, 3H, J=7.2 Hz).

Step 3: Synthesis of(R)-3-(2-sec-butoxy-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

(R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt(69 mg, 0.24 mmol) was reacted with3-(2-sec-butoxy-4-fluoro-phenyl)-acrylic acid (55 mg, 0.23 mmol), NMM(0.15 ml) and DMTMM (75 mg) at room temperature overnight to yield thetitle compound (15 mg, 14%) after column chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.87 (d, 1H, J=15.6 Hz), 7.43 (m, 1H), 6.99(d, 1H, J=8.7 Hz), 6.64 (m, 2H), 6.41 (d, 1H, J=15.6 Hz), 6.11 (s, 1H),5.80 (d, 1H, J=7.5 Hz), 5.17 (t, 1H), 4.33 (m, 1H, J=6.0 Hz), 3.19 (s,3H), 1.78 (m, 1H), 1.67 (m, 1H), 1.49 (d, 3H, J=7.2 Hz), 1.32 (d, 3H,J=6.0 Hz), 0.98 (t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 469

Example 413-(2-sec-Butoxy-4-fluoro-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)-acrylamide

N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide, HCl salt (42mg, 0.15 mmol) was reacted with 3-(4-fluoro-2-propoxy-phenyl)-acrylicacid (34 mg, 0.14 mmol), NMM (0.15 ml) and DMTMM (43 mg) at roomtemperature overnight to yield the title compound (15 mg, 23%) aftercolumn chromatography (Hex/EtOAc=1/1).

¹H NMR (300 MHz, CDCl₃): δ 7.89 (d, 1H, J=15.9 Hz), 7.44 (m, 1H), 6.97(d, 1H, J=8.4 Hz), 6.65 (s, 1H), 6.60 (d, 1H, J=9.3 Hz), 6.47 (d, 1H,J=15.6 Hz), 6.08 (s, 1H), 6.00 (s, 1H, J=7.5 Hz), 4.53 (d, 2H, J=6.0Hz), 4.34 (m, 1H, J=6.0 Hz), 3.20 (s, 3H), 1.78 (m, 1H), 1.67 (m, 1H),1.49 (d, 3H, J=7.2 Hz), 1.34 (d, 3H, J=6.0 Hz), 0.99 (t, 3H, J=7.2 Hz).

Example 42(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-ethylamino-4-fluoro-phenyl)-acrylamide

Step 1: Synthesis of N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide

To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.20 g,1.01 mmol), acetaldehyde (86 μL, 1.53 mmol), and AcOH (87 μL, 2.1 mmol)in dichloromethane (20 mL) was added sodium triacetoxyborohydride (430mg, 2.03 mmol) at 5° C. The mixture was stirred for 90 minutes at thesame temperature and then 40 minutes at room temperature. The reactionwas quenched by adding water. The organic layer was washed withsaturated aqueous NaHCO₃ solution and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure togive N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamidequantitatively.

¹H NMR (300 MHz, CDCl₃): δ 7.43˜7.38 (m, 1H), 6.35˜6.25 (m, 2H), 3.58(s, 3H), 3.33 (s, 3H), 3.16˜3.07 (m, 2H), 1.27 (t, 3H, J=6.9 Hz).

Step 2: Synthesis of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acidmethyl ester

To a solution of N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide(0.23 g, 1.02 mmol) in THF (4 mL) was added dropwise LiAlH₄ (1 M in THF,0.51 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C.and then quenched by adding saturated aqueous KHSO₄ solution. Themixture was diluted with EtOAc, washed with 3 N HCl, and brine, driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was reacted with methyl(triphenylphosphoranylidene)acetate (375 mg, 1.12 mmol) in toluene (4mL) overnight at 100° C. The mixture was washed with water, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give the title compound (0.13 g, 57%) after purification bycolumn chromatography (EtOAc:hexane=1:10).

¹H NMR (300 MHz, CDCl₃): δ 7.73 (d, 1H, J=15.6 Hz), 7.32 (t, 1H, J=7.2Hz), 6.42˜6.32 (m, 2H), 6.27 (d, 1H, J=15.6 Hz), 4.09 (br, 1H), 3.80 (s,3H), 3.19˜3.15 (m, 2H), 1.31 (t, 3H, J=7.2 Hz).

Step 3: Synthesis of(R)—N-[1-(3,5-Difluoro-4-methanesulfonylaminophenyl)ethyl]-3-(4-fluoro-2-ethylaminophenyl)acrylamide

To a solution of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid methylester (128 mg, 0.57 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 NLiOH (4 mL). The mixture was stirred for 2 hours at room temperature,concentrated under reduced pressure, and then acidified with 3 N HCl.The mixture was diluted with EtOAc, washed with water, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid (88 mg,73%) after purification by crystallization form EtOAc and hexane. To amixture of 3-(4-fluoro-2-ethylamino-phenyl)-acrylic acid (40 mg, 0.19mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethylaminehydrochloride (55 mg, 0.19 mmol) and N-methylmorpholine (31 μL, 0.28mmol) in THF (4 mL) was added4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloridehydrate (DMTMM, 58 mg, 0.21 mmol). The mixture was stirred overnight atroom temperature and then concentrated under reduced pressure. Theresidue was diluted with EtOAc and water, washed with 2 N HCl and brine,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to give the title compound (4.9 mg, 6%) afterpurification by column chromatography (EtOAc:hexane=1:10 to 2:1).

¹H NMR (300 MHz, CDCl₃+DMSO-d6): δ 9.05 (br, 1H), 8.00 (d, 1H, J=7.8Hz), 7.62 (d, 1H, J=15.3 Hz), 7.29 (t, 1H, J=7.8 Hz), 7.01 (d, 2H, J=8.4Hz), 6.40 (d, 1 H, J=15.3 Hz), 6.37˜6.28 (m, 2H), 5.13 (t, 1H, J=6.9Hz), 4.50 (bs, 1H), 3.20-3.10 (m, 2H), 3.08 (s, 3H), 1.48 (d, 3H, J=6.9Hz), 1.28 (t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 440

Example 43N-(3,5-Difluoro-4-methanesulfonylaminobenzyl)-3-(4-fluoro-2-ethylaminophenyl)acrylamide

To a mixture of 4-fluoro-2-ethylaminocinnamic acid (40 mg, 0.19 mmol),(3,5-difluoro-4-methanesulfonylamino)benzylamine hydrochloride (52 mg,0.19 mmol) and N-methylmorpholine (31 μL, 0.28 mmol) in THF (4 mL) wasadded 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloridehydrate (DMTMM, 58 mg, 0.21 mmol). The mixture was stirred overnight atroom temperature and then concentrated under reduced pressure. Theresidue was diluted with EtOAc and water, and the organic layer waswashed with 2 N HCl and brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure to give the titlecompound (17 mg, 21%) after trituration with ethyl ether.

¹H NMR (300 MHz, CDCl₃+DMSO-d6): δ 9.07 (bs, 1H), 8.14 (br, 1H), 7.66(d, 1H, J=15.6 Hz), 7.31 (t, 1H, J=7.2 Hz), 6.98 (d, 2H, J=8.1 Hz), 6.40(d, 1H, J=15.3 Hz), 6.37˜6.29 (m, 2H), 4.55 (br, 1H), 4.47 (d, 2H, J=5.7Hz), 3.18˜3.12 (m, 2H), 3.09 (s, 3H), 1.29 (t, 3H, J=7.2 Hz).

Example 44(R)—N-(2-Fluoro-4-{1-[3-(2-propyl-4-trifluoromethyl-phenyl)-allylamino]-ethyl}-phenyl)-methanesulfonamide

(R)—N-[4-(1-Amino-ethyl)-2-fluoro-phenyl]-methanesulfonamide, HCl salt(31 mg, 0.12 mmol) was reacted with3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (25 mg, 0.097 mmol)to give the title compound (32 mg, 70%) after purification byrecrystallization from Hex/EtOAc.

¹H NMR (300 MHz, DMSO-d6): δ 8.70 (d, 1H, J=7.5 Hz), 7.66 (m, 3H), 7.33(t, 1H, J=8.1 Hz), 7.23 (d, 1H, J=11.7 Hz), 7.15 (d, 1H, J=8.4 Hz), 6.70(d, 1H, J=15.6 Hz), 5.02 (m, 1H), 2.98 (s, 3H), 2.75 (t, 2H, J=6.9 Hz),1.50 (m, 2H), 1.40 (d, 3H, J=6.9 Hz), 1.32 (m, 2H), 0.89 (t, 3H, J=7.5Hz).

Example 45(R)-3-(2-Butylamino-4-fluoro-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

Step 1: Synthesis ofN-methoxy-N-methyl-4-fluoro-2-n-buthylamino-benzamide

To a solution of N-methoxy-N-methyl-2-amino-4-fluorobezoic acid amide(0.35 g, 1.75 mmol), butyrylaldehyde (0.23 mL, 2.62 mmol), and AcOH(0.15 mL, 2.62 mmol) in dichloromethane (20 mL) was added sodiumtriacetoxyborohydride (0.74 g, 3.49 mmol) at 5° C. The mixture wasstirred for 5 hours at the same temperature and overnight at roomtemperature. The reaction was quenched by adding water. The organiclayer was washed with saturated aqueous NaHCO₃ solution and brine, driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to give the title compound quantitatively.

¹H NMR (300 MHz, CDCl₃): δ 7.43˜7.38 (m, 1H), 6.35˜6.24 (m, 2H), 3.58(s, 3H), 3.33 (s, 3H), 3.10˜3.02 (m, 2H), 1.67˜1.35 (m, 4H), 0.95 (t,3H, J=7.2 Hz).

Step 2: Synthesis of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acidmethyl ester

To a solution of N-methoxy-N-methyl-4-fluoro-2-n-butylamino-benzamide(0.5 g, 1.97 mmol) in THF (8 mL) was added dropwise LiAlH₄ (1 M in THF,1.0 mL) at −45° C. The mixture was stirred for 40 minutes at −35° C. andthen quenched by adding saturated aqueous KHSO₄ solution. The mixturewas diluted with EtOAc, washed with 3 N HCl, and brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was reacted with methyl(triphenylphosphoranylidene)acetate (725 mg, 2.17 mmol) in toluene (4mL) overnight at 100° C. The mixture was washed with water, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give the title compound (0.15 g, 30%) after purification bycolumn chromatography (EtOAc:hexane=1:10).

¹H NMR (300 MHz, CDCl₃): δ 7.71 (d, 1H, J=15.9 Hz), 7.31 (t, 1H, J=8.4Hz), 6.42˜6.31 (m, 2H), 6.26 (d, 1H, J=15.9 Hz), 4.13 (br, 1H),3.15˜3.09 (m, 2H), 1.71˜1.61 (m, 2H), 1.49˜1.41 (m, 2H), 0.98 (t, 3H,J=7.2 Hz).

Step 3: Synthesis of(R)—N-[1-(3,5-Difluoro-4-methanesulfonylaminophenyl)ethyl]-3-(4-fluoro-2-n-butylaminophenyl)acrylamide

To a solution of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid methylester (145 mg, 0.58 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 NLiOH (4 mL). The mixture was stirred for 2 hours at room temperature,concentrated under reduced pressure, and then acidified with 3 N HCl.The mixture was diluted with EtOAc, washed with water, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid (120 mg,88%) after purification by crystallization form EtOAc and hexane. To amixture of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid (52 mg, 0.22mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethylaminehydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33mmol) in THF (5 mL) was added4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloridehydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight atroom temperature and then concentrated under reduced pressure. Theresidue was diluted with EtOAc and water, washed with 2 N HCl and brine,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to give the title compound (4.5 mg, 4%) aftertrituration with ethyl ether. 2:1).

¹H NMR (300 MHz, CDCl₃): δ 7.78 (d, 1H, J=14.7 Hz), 7.30 (t, 1H, J=6.9Hz), 6.95˜6.90 (m, 3H), 6.36˜6.30 (m, 2H), 6.23 (d, 1H, J=14.7 Hz), 5.95(d, 1H, J=6.6 Hz), 5.11 (t, 1H, J=6.9 Hz), 4.50 (bs, 1H), 3.18 (s, 3H),3.10 (t, 2H, J=6.9 Hz), 1.68˜1.58 (m, 2H), 1.48 (d, 3H, J=6.9 Hz),1.43˜1.38 (m, 2H), 0.95 (t, 3H, J=7.2 Hz).

ESI [M−H]⁻: 468

Example 463-(2-Butylamino-4-fluoro-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)-acrylamide

To a mixture of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid (52 mg,0.22 mmol), (3,5-difluoro-4-methanesulfonylamino)benzylaminehydrochloride (61 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33mmol) in THF (5 mL) was added4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloridehydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight atroom temperature and then concentrated under reduced pressure. Theresidue was diluted with EtOAc and water, washed with 2 N HCl and brine,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to give the title compound (45 mg, 45%) aftertrituration with ethyl ether.

¹H NMR (300 MHz, CDCl₃+DMSO-d6): δ 8.71 (bs, 1H), 7.73 (br, 1H), 7.68(d, 1H, J=15.6 Hz), 7.30 (t, 1H, J=7.5 Hz), 6.97 (d, 2H, J=8.4 Hz),6.40˜6.30 (m, 3H), 4.49 (d, 2H, J=6 Hz), 3.14˜3.09 (m, 5H), 1.69˜1.59(m, 2H), 1.50˜1.38 (m, 2H), 0.96 (t, 3H, J=7.5 Hz).

Example 47(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-isobutyl-4-trifluoromethyl-phenyl)-acrylamide

3-(2-Isopropyl-4-trifluoromethyl-phenyl)-acrylic acid was obtained bythe procedure in example 21.

(R)—N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (55 mg, 0.20 mmol) was reacted with3-(2-isobutyl-4-trifluoromethyl-phenyl)-acrylic acid (40 mg, 0.15 mmol)to give the title compound (18 mg, 24%) after purification byrecrystallization from ether.

¹H NMR (300 MHz, DMSO-d⁶): δ 8.74 (d, 1H, J=7.8 Hz), 7.67 (m, 4H), 7.17(d, 2H, J=8.7 Hz), 6.70 (d, 1H, J=15.6 Hz), 5.03 (m, 1H), 3.04 (s, 3H),2.78 (t, 2H), 2.67 (m, 1H), 1.47 (m, 2H), 1.41 (d, 3H, J=6.9 Hz), 1.31(m, 2H), 0.87 (m, 9H).

Example 48(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

Step 1: Synthesis of2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid

To a suspension ofN-methoxy-N-methyl-2-propyl-4-trifluoromethyl-benzamide (150 mg, 0.58mmol) in THF (10 mL) was added dropwise 1.0M LiAlH₄ (0.30 mL, 0.30 mmol)at −78° C. The mixture was warmed up to −20° C. and stirred for 30 mins.An aqueous solution of sodium potassium tartarate (10% w/v) was added tothe reaction mixture and the resulting mixture was vigorously stirredfor 30 mins, to which was added Et₂O. After separation of two phases,the aqueous layer was extracted three times with ether and the combinedorganic layer was washed with brine, dried over anhyd. MgSO₄, filteredand concentrated under reduced pressure. The product was vacuum dried toyield the 2-propyl-4-trifluoromethyl-benzaldehyde.

To an ice-cold suspension of NaH (60% in mineral oil, 45 mg, 1.13 mmol)in THF (2 mL) was added triethyl-2-phosphonopropionate (0.16 mL, 0.75mmol), and the resulting mixture was stirred for 10 mins at ambienttemperature. A solution of aldehyde obtained above in THF was added tothe reaction mixture and the resulting mixture was stirred for 3 hrs atambient temperature. The reaction mixture was diluted with water andEtOAc, and the aqueous layer was extracted three times with EtOAc. Thecombined organic layer was dried over anhydrous MgSO₄ and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography (gradient 12% to 100% EtOAc in Hex) to give2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid ethyl ester(68 mg, 39%).

To a suspension of2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid ethyl ester(68 mg, 0.23 mmol) in THF (1 mL) was added a solution of 1N—LiOH (10ml), and the mixture was stirred for 3 hours at room temperature. Theresulting residue was dissolved in H₂O and then washed three times withEtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted threetimes with methylene chloride and then dried over anhydrous MgSO₄ andconcentrated in vacuo to give the title compound (60 mg, 96%).

¹H NMR (300 MHz, CDCl₃): δ 7.91 (s, 1H), 7.48 (bs, 2H), 7.30 (d, 1H,J=8.7 Hz), 2.63 (t, 2H, J=8.1 Hz), 1.96 (s, 3H), 1.61 (m, 2H), 0.95 (t,3H, J=7.2 Hz).

Step 2: Synthesis of(R)—N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

To a suspension of(R)—N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (30 mg, 0.11 mmol) in THF (2 mL) was added N-methylmorpholine (23μl, 0.21 mmol). The mixture was stirred for 5 minutes, to which wereadded 2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (22mg, 0.081 mmol) and4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloridehydrate (DMTMM, 27 mg, 0.098 mmol). The mixture was stirred overnight atroom temperature and was concentrated under reduced pressure. Theresidue was diluted with EtOAc and water. The organic layer was washedwith saturated sodium bicarbonate, 1N HCl and brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The crude residue was purified by column chromatography(gradient 12% to 100% EtOAc in Hex) to give title compound (18 mg, 44%).

¹H NMR (300 MHz, DMSO-d6): δ 8.41 (d, 1H, J=7.8 Hz), 7.58 (m, 2H), 7.41(m, 2H), 7.13 (d, 2H, J=8.4 Hz), 5.04 (m, 1H), 2.97 (s, 3H), 2.62 (t,2H), 1.86 (s, 3H), 1.52 (m, 2H), 1.43 (d, 3H, J=6.9 Hz), 0.87 (t, 3H,J=7.2 Hz).

Example 49(R)—N-[1-(3-Fluoro-4-methanesulfonylamino-phenyl)-ethyl]-2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-[4-(1-Amino-ethyl)-2-fluoro-phenyl]-methanesulfonamide, HCl salt(52 mg, 0.19 mmol) was reacted with2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid (40 mg, 0.15mmol) to give the title compound (68 mg, 93%) after purification bycolumn chromatography (gradient 12% to 100% EtOAc in Hex).

¹H NMR (300 MHz, DMSO-d6): δ 9.51 (bs, 1H), 8.41 (d, 1H, J=7.8 Hz), 7.58(m, 2H), 7.29 (m, 5H), 5.06 (m, 1H), 3.00 (s, 3H), 2.60 (t, 2H), 1.86(s, 3H), 1.50 (m, 2H), 1.44 (d, 3H, J=7.2 Hz), 0.87 (t, 3H, J=7.5 Hz).

Example 50(R)-3-(2-Cyclohexylmethoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

Step 1: Synthesis of 2-cyclohexylmethoxy-4-trifluoromethyl-benzoic acidcyclohexylmethyl ester

2-Hydroxy-4-trifluoromethyl-benzoic acid (246 mg, 1.19 mmol) was reactedwith toluene-4-sulfonic acid cyclohexylmethyl ester (640 mg, 2.34 mmol)as described above to give the title compound (470 mg, 99%) afterpurification by column chromatography.

¹H NMR (300 MHz, CDCl₃): δ 7.83 (d, 1H, J=7.8 Hz), 7.20 (d, 1H, J=7.8Hz), 7.13 (s, 1H), 4.13 (d, 2H, J=6.6 Hz), 3.84 (d, 2H, J=5.7 Hz),2.04˜1.74 (m, 12H), 1.33-1.02 (m, 10H).

Step 2: Synthesis of2-cyclohexylmethoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide

2-Cyclohexylmethoxy-4-trifluoromethyl-benzoic acid cyclohexylmethylester (528 mg, 1.33 mmol) was reacted with 1N LiOH (2.65 mg, 2.65 mmol)as described above to give 2-cyclohexylmethoxy-4-trifluoromethyl-benzoicacid (361 mg, 90%) after drying by vacuum.

2-Cyclohexylmethoxy-4-trifluoromethyl-benzoic acid (361 mg, 1.19 mmol)was reacted with N,O-dimethylhydroxyamine, HCl salt (128 mg, 1.31 mmol)as described above to give the title compound (363 mg, 88%) afterpurification by vacuum dry.

¹H NMR (300 MHz, CDCl₃): δ 7.36 (s, 1H), 7.23 (d, 1H, J=7.5 Hz), 7.10(s, 1H), 3.83 (d, 2H, J=5.7 Hz), 3.42 (s, 3H), 3.37 (s, 3H), 1.84˜1.73(m, 6H), 1.49˜1.05 (m, 5H).

Step 3: Synthesis of3-(2-cyclohexylmethoxy-4-trifluoromethyl-phenyl)-acrylic acid methylester

2-Cyclohexylmethoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (363mg, 1.05 mmol) was processed by LAH reduction and wittig reaction asdescribed above to give the title compound (250 mg, 69%) afterpurification by column chromatography (n-Hex/EtOAc=20/1).

¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, 1H, J=16.2 Hz), 7.58 (d, 1H, J=7.8Hz), 7.19 (d, 1H, J=7.8 Hz), 7.09 (s, 1H), 6.60 (d, 1H, J=16.2 Hz), 3.86(d, 2H, J=5.7 Hz), 3.82 (s, 3H), 1.91˜1.77 (m, 6H), 1.43˜1.05 (m, 5H).

Step 4: Synthesis of3-(2-cyclohexylmethoxy-4-trifluoromethyl-phenyl)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-acrylamide

N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HCl salt(28.8 mg, 0.101 mmol) was reacted with3-(2-cyclohexylmethoxy-4-trifluoromethyl-phenyl)-acrylic acid (30 mg,0.091 mmol) to give the title compound (33 mg, 65%) after purificationby column chromatography.

¹H NMR (300 MHz, CDCl₃): δ 7.88 (d, 1H, J=15.6 Hz), 7.50 (d, 1H, J=8.1Hz), 7.12 (d, 1H, J=8.1 Hz), 7.03 (s, 1H), 6.94 (d, 2H, J=8.4 Hz), 6.51(d, 1H, J=15.9 Hz), 6.04 (s, 1H), 5.82 (d, 1H, J=7.2 Hz), 5.17-5.10 (m,1H), 3.80 (d, 1H, J=5.7 Hz), 3.15 (s, 3H), 1.86-1.65 (m, 6H), 1.47 (d,3H, J=6.9 Hz), 1.28-1.02 (m, 5H).

Example 51N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-piperidin-1-yl-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-3,5-difluoro-phenyl)-methanesulfonamide, HCl salt (59mg, 0.217 mmol) was reacted with3-(2-piperid-1-yl-4-trifluoromethyl-phenyl)-acrylic acid (65 mg, 0.217mmol) to give the title compound (25 mg, 22%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, 1H, J=15.6 Hz), 7.60 (m, 2H), 6.99(m, 2H), 6.79 (d, 1H, J=8.4 Hz), 6.46 (d, 1H, J=15.6 Hz), 6.00 (s, 1H),4.37 (d, 2H, J=6.3 Hz), 3.21 (s, 3H), 2.92 (m, 4H), 1.77 (m, H), 1.61(m, 4H)

Example 52(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-3-(2-piperidin-1-yl-4-trifluoromethyl-phenyl)-acrylamide

(R)—N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, HClsalt (129 mg, 0.451 mmol) was reacted with3-(2-piperid-1-yl-4-trifluoromethyl-phenyl)-acrylic acid (135 mg, 0.451mmol) to give the title compound (65 mg, 27%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, CDCl₃): δ 7.94 (d, 1H, J=15.9 Hz), 7.55 (d, 1H, J=8.4Hz), 7.23 (m, 2H), 7.01 (m, 2H), 6.43 (d, 1H, J=15.6 Hz), 5.99 (s, 1H),5.83 (s, 1H), 5.20 (m, 1H), 3.21 (s, 3H), 2.92 (m, 4H), 1.76 (m, 4H),1.59 (m, 2H), 1.53 (d, 3H, J=6.6 Hz).

Example 53(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(4-fluoro-2-propyl-phenyl)-acrylamide

3-(4-Fluoro-2-propyl-phenyl)-acrylic acid was prepared as describedabove. (R)—N-(4-Aminoethyl-2,6-difluoro-phenyl)-methanesulfonamide, HClsalt (28 mg, 0.097 mmol) was reacted with3-(4-fluoro-2-propyl-phenyl)-acrylic acid (15 mg, 0.072 mmol), NMM (0.20ml) and DMTMM (36 mg) at room temperature overnight to yield the titlecompound (12 mg, 38%) after column chromatography (Hex/EtOAc=3/2).

¹H NMR (300 MHz, CDCl₃): δ 7.91 (d, 1H, J=15.3 Hz), 7.00 (d, 1H, J=8.4Hz), 7.48 (m, 1H), 6.92 (m, 2H), 6.25 (d, 1H, J=15.3 Hz), 6.05 (br, 1H),5.82 (d, 1H, J=6.9 Hz), 5.17 (t, 1H, J=7.1 Hz), 3.20 (s, 1H), 2.72 (t,2H, J=7.5 Hz), 1.60 (m, 2H), 0.95 (t, 3H, J=7.2 Hz)

Example 54N-(3-Fluoro-4-methanesulfonylamino-5-vinyl-benzyl)-3-(2-isopropylamino-4-trifluoromethyl-phenyl)-acrylamide

N-(4-Aminomethyl-2,5-difluoro-phenyl)-methanesulfonamide, HCl salt (43mg, 0.154 mmol) was reacted with3-(2-isopropylamino-4-trifluoro-phenyl)-acrylic acid (42 mg, 0.154 mmol)to give the title compound (34 mg, 42%) after purification bycrystallization from Hex/EtOAc.

¹H NMR (300 MHz, DMSO-d6): δ 8.71 (s, 1H), 7.70 (d, 1H, J=15.3 Hz), 7.50(m, 2H), 7.10 (m, 3H), 6.83 (s, 1H), 6.57 (d, 1H, J=15.3 Hz), 5.85 (m,1H), 5.70 (m, 1H), 5.42 (m, 1H), 4.42 (d, 2H, J=5.4 Hz), 3.58 (m, 1H),2.98 (s, 3H), 1.18 (d, 6H, J=6.0 Hz).

ESI [M−H]⁻: 498

Example 55(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-propionamide

(R)—N-[1-(3,5-Difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide(12 mg) was reduced with Pd/C (15 mg) under hydrogen atmosphere to yieldtitle compound (7 mg, 60%).

¹H NMR (300 MHz, CDCl₃): δ 7.02 (d, 1H, J=7.5 Hz), 6.95 (d, 1H, J=8.7Hz), 6.87˜6.71 (m, 3H), 6.17 (br, 1H), 5.62 (d, 1H, J=7.8 Hz), 4.96 (t,1H, J=7.2 Hz), 3.15 (s, 3H), 3.00 (m, 2H), 2.83 (m, 2H), 2.47 (m, 2H),1.32 (d, 3H, J=6.6 Hz), 0.96 (t, 3H, J=7.5 Hz).

Example 56N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-propionamide

N-(3,5-Difluoro-4-methanesulfonylamino-benzyl)-3-(2-propylamino-4-trifluoromethyl-phenyl)-acrylamide(20 mg, 0.041 mmol) was reduced with Pd/C under hydrogen atmosphere toyield title compound (12 mg, 59%).

¹H NMR (300 MHz, CDCl₃): δ 7.08 (d, 1H, J=7.5 Hz), 6.95 (d, 1H, J=8.4Hz), 36.87 (d, 1H, J=7.8 Hz), 6.78 (s, 1H), 6.76 (m, 1H), 6.29 (s, 1H),5.93 (t, 1H), 4.36 (d, 2H, J=6.3 Hz), 3.19 (s, 3H), 3.09 (m, 2H), 2.91(m, 2H), 2.55 (m, 2H), 1.70 (m, 2H), 1.02 (t, 3H, J=7.5 Hz)

Experimental Example Biological Potency Test 1. ⁴⁵Ca Influx Test

1) Separation of Spinal Dorsal Root Ganglia (DRG) in Newborn Rats andPrimary Culture Thereof.

Neonatal (2-3 day old or younger than 2-3 day old) SD rats were put inice for 5 minutes to anesthetize and disinfected with 70% ethanol. DRGof all part of spinal cord were dissected (Wood et al., 1988, J.Neurosci. 8, pp 3208-3220) and collected in DME/F12 medium to which 1.2g/l sodium bicarbonate and 50 mg/l gentamycin were added. The DRG wereincubated sequentially at 37° C. for 30 mins in 200 U/ml collagenase and2.5 mg/ml trypsin, separately. The ganglia were washed twice withDME/F12 medium supplemented with 10% horse serum, triturated through afire-polished Pasteur pipette, filtered through Nitex 80 membrane toobtain single cell suspension and the suspension was washed once more.This was subjected to centrifugation, then resuspended in cell culturemedium at certain level of cell density. As the cell culture medium,DME/F12 medium supplemented with 10% horse serum was diluted withidentical medium conditioned by C6 glioma cells 2 days on a confluentmonolayer (1:1), and NGF (Nerve Growth Factor) was added to adjust 200ng/ml as final concentration. After the cells were grown 2 days inmedium where cytosine arabinoside (Ara-C, 100 μM) was added to killdividing normeuronal cells, medium was changed to one without Ara-C. Theresuspended cells were plated at a density of 1500-2000 neurons/wellonto Terasaki plates previously coated with 10 mg/ml poly-D-ornithine.

2) ⁴⁵Ca Influx Experiments

DRG nerve cells from the primary culture of 2 days were equilibrated bywashing 4 times with HEPES (10 mM, pH 7.4)-buffered Ca ²⁺, Mg²⁺-freeHBSS(H-HBSS). The solution in each well was removed from the individualwell. Medium containing the test compound plus capsaicin (finalconcentration 0.5 μM) and ⁴⁵Ca (final concentration 10 μCi/ml) in H-HBSSwas added to each well and incubated at room temperature for 10 mins.Terasaki plates were washed five times with H-HBSS and dried at roomtemperature. To each well, 0.3% SDS (10 μl) was added to elute ⁴⁵Ca.After the addition of scintillation cocktail of into each well, theamount of ⁴⁵Ca influx into neuron was measured by countingradioactivity. Antagonistic activities of test compounds againstvanilloid receptor were calculated as percent of the inhibition ofmaximal response of capsaicin at a concentration of 0.5 μM. The resultsare displayed in Table 1 below.

TABLE 1 Results of Calcium Influx Test Antagonist Calcium Uptake TestExamples (IC₅₀, μM) 1 0.019 2 0.17 3 0.12 4 0.38 5 0.12 6 0.026 7 0.11 80.85 9 0.34 10 0.050 11 0.062 12 0.15 13 0.12 14 0.24 15 2.4 16 0.22 170.14 18 0.083 19 0.16 20 0.15 21 0.019 22 0.16 23 0.27 24 0.044 25 0.1726 0.047 27 0.17 28 1.1 29 0.16 30 0.41 31 0.11 32 2.2 33 0.15 34 0.9835 0.092 36 0.046 37 1.7 38 1.1 39 0.022 40 0.10 41 0.55 42 0.11 43 0.3244 0.091 45 0.065 46 0.18 47 0.094 48 0.53 49 1.4 50 0.21 51 3.3 52 0.3453 0.17 54 0.027 55 0.19 56 0.35

2. Analgesic Activity Test: Mouse Writhing Test by Inducing withPhenyl-p-Quinone

Male ICR mice (mean body weight 25 g) were maintained in a controlledlighting environment (12 h on/12 h off) for experiment. Animals receivedan intraperitoneal injection of 0.3 ml of the chemical irritantphenyl-p-quinone (dissolved in saline containing 5% ethanol to be a doseof 4.5 mg/kg) and 6 mins later, the number of abdominal constrictionswas counted in the subsequent 6 mins period. Animals (10 animals/group)received 0.2 ml of test compounds solution in vehicle of ethanol/Tween80/saline (Oct. 10, 1980) intraperitoneally 30 min before the injectionof phenyl-p-quinone. In the case of oral administration, 0.2 ml of testcompounds solution in vehicle of ethanol/Tween 80/saline (5/5/90) wereadministered 54 min prior to the 0.2 ml of 0.02% phenyl-p-quinoneinjection. A reduction in the number of writhes responding to the testdrug compound relative to the number responding in saline control groupwas considered to be indicative of an analgesic effect. Analgesic effectwas calculated by % inhibition equation (% inhibition=(C−T)/C×100),wherein C and T represent the number of writhes in control andcompound-treated group, respectively. Most examples of the presentdisclosure having good in vitro activities, were tested at various doses(ranging from 0.3 to 3 mg/kg) and all compounds tested in vivo showedanalgesic effects from 8 to 59% inhibition at each dose, respectively.

3. PK Study

Pharmacokinetics of compounds in rats were analyzed using the followingexperiment. Rats were fasted overnight prior to administration and untilapproximately 4 hours after administration. Rats were given a singleoral administration of compound at same dose. Administration volume was10 ml/kg. Blood samples were collected from the retro-orbital sinus atvarious times over the following 7 hrs Immediately after eachcollection, plasmas were separated from blood cells by centrifugationand stored at −20° C. until the analysis was performed. The plasmasamples were analyzed using a reverse phase high-performancechromatography (HPLC) method. The results are displayed in table 2below.

TABLE 2 PK results for the compound having CF3-phenyl with metasubstituent Cmax Tmax AUCpo T1/2 Ex # Structure IC50 (mcg/ml) (hour)(mcg hr ml-1) (hour)  1

0.019 0.466 3.500  1.939 1.399  2

0.17  1.417 2.000  7.152 3.551  5

0.12  2.631 3.50  22.456 4.300 21

0.019 2.716 2.000 16.424 3.501 22

0.16  3.656 2.000 19.227 2.581 24

0.044 1.187 2.000  5.693 2.079

4. Comparative Examples

As shown in Tables 2 and 3, the PK properties of the compounds offormula (I) of the present disclosure surprisingly have superior PKcharacteristics compared to compounds with a tert-butyl phenyl partialstructure, with or without other substituents on the phenyl group, whichwere at least in part disclosed in the art, e.g. in WO 06/101318 or WO06/101321 (also refer Table 3). Substantial increases in absorption andapparent half-life were observed by the replacement of tert-butyl phenylby F-phenyl or CF₃-phenyl (see Table 2 vs 3).

TABLE 3 PK results for the compound having tert-butyl-phenyl IC50 CmaxTmax AUCpo T1/2 Ex # Structure (μM) (mcg/ml) (hour) (mcg hr ml-1) (hour)Comp Cpd A (Ex 15^(a))

0.034 <0.100 —b —b —b Comp Cpd B (Ex 4^(c))

0.31    0.069 0.500 0.072 0.462 Comp Cpd C (Ex 34^(a))

0.17  <0.100 —b —b —b Comp Cpd D

0.085 <0.100 —b —b —b Comp Cpd E

2.3  <0.100 —b —b —b ^(a)Example number in WO 06/101318 b could not bedetermined due to low plasma concentration (detection limit: 0.100mcg/ml). ^(c)Example number in WO 06/101321

As shown in Tables 2 and 4, the compounds of formula (I) of the presentdisclosure have superior IC₅₀ values and in some cases also improved PKcharacteristics compared to compounds with a CF₃-phenyl partialstructure but without additional substituents on the phenyl group, whichwere at least in part disclosed in the art, e.g. in WO 06/101318 or WO06/101321. Surprisingly, the introduction of an additional substituentin ortho position of the phenyl's attachment position to the cinnamoylbackbone confers improved VR1 activity to the compounds. For example,whilst comparative compound “G” has an IC50 value of more than 10 μM,the compounds 1, 3,5-7,10,16-18, 21, 24, 26, 31, 39, 47, 50, and 52 ofthe present disclosure which all differ from “G” only by additionalsubstituent(s) on phenyl group, all have IC50 values in a range between0.019 and 0.34 μM. In addition, compound “G” shows only poorPK-properties, while all tested compounds of the present disclosureshowed improved PK properties (in terms of T max and AUC). Likewise,while comparative compound “F” has a moderate IC₅₀ value of 0.57 μM, theIC₅₀ values of the corresponding examples of the present disclosure Ex12 (0.15 μM) and 54 (0.027 μM) are significantly improved.

TABLE 4 PK results for the compound having CF3-phenyl IC50 Cmax TmaxAUCpo T_(1/2) Ex # Structure (μM) (mcg/ml) (hour) (mcg hr ml-1) (hour)Comp Cpd F (Ex 18 ^(a))

0.57   5.001 2.000 40.123 4.589 Comp Cpd G

>10 <0.100 —^(b) —^(b) —^(b) ^(a) Example number in WO 06/101318 ^(b)could not be determined due to low plasma concentration (detectionlimit: 0.100 mcg/ml).

In summary, the presently disclosed compounds of formula (I) show asignificantly improved “balance” between VR1 activity and PK propertiescompared to the compounds disclosed in the art.

INDUSTRIAL APPLICABILITY

As explained above, the compound according to the present disclosure isuseful to prevent or to treat pain, inflammatory disease of the joints,neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration,stroke, urinary bladder hypersensitivity including urinary incontinence,cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) andinflammatory bowel disease (IBD), fecal urgency, gastro-esophagealreflux disease (GERD), Crohn's disease, asthma, chronic obstructivepulmonary disease, cough, neurotic/allergic/inflammatory skin disease,psoriasis, pruritus, prurigo, irritation of skin, eye or mucousmembrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodicvertigo, cardiac diseases such as myocardial ischemia, hairgrowth-related disorders such as effluvium, alopecia, rhinitis, andpancreatitis.

More specifically, the compound according to the present disclosure isuseful to preventing and treating of pain, which is or which isassociated with a condition selected from the group consisting ofosteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabeticneuropathic pain, post-operative pain, dental pain, non-inflammatorymusculoskeletal pain (including fibromyalgia, myofascial pain syndromeand back pain), migraine, and other types of headaches.

1-15. (canceled)
 16. A pharmaceutical composition comprising a compoundof formula (I), an isomer, or a pharmaceutically acceptable salt thereof

wherein, R₁ is hydrogen, methyl, or ethyl; R₂ and R₃ are independentlyhydrogen, halogen, cyano, methyl, ethyl, methoxy, trifluoromethyl,vinyl, or acetylenyl; R₄ is trifluoromethyl or fluoro; R₅ is C2-C5alkyl, C2-C5 alkoxy, C1-C2 alkoxy (C1-C3) alkoxy, C1-C2 alkoxy (C1-C3)alkylamino, C2-C5 alkylamino, di(C1-C3 alkyl)amino, C3-C6cycloalkylamino, C3-C6 cycloalkoxy, or (C3-C6)cycloalkyl(C1-C3)alkyloxy;and R₆ is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 alkylamino, asan active ingredient and a pharmaceutically acceptable carrier.
 17. Thepharmaceutical composition according to claim 16, for preventing ortreating a condition associated with the pathological stimulation and/oraberrant expression of vanilloid receptors.
 18. The pharmaceuticalcomposition according to claim 16, for treating a condition selectedfrom the group consisting of pain, inflammatory disease of the joints,neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration,stroke, urinary bladder hypersensitivity including urinary incontinence,cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) andinflammatory bowel disease (IBD), fecal urgency, gastro-esophagealreflux disease (GERD), Crohn's disease, asthma, chronic obstructivepulmonary disease, cough, neurotic/allergic/inflammatory skin disease,psoriasis, pruritus, prurigo, irritation of skin, eye or mucousmembrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodicvertigo, cardiac diseases such as myocardial ischemia, hairgrowth-related disorders such as effluvium, alopecia, rhinitis, andpancreatitis.
 19. The pharmaceutical composition according to claim 18,wherein the pain is or is associated with a condition selected from thegroup consisting of osteoarthritis, rheumatoid arthritis, ankylosingspondylitis, diabetic neuropathic pain, post-operative pain, dentalpain, non-inflammatory musculoskeletal pain (including fibromyalgia,myofascial pain syndrome and back pain), visceral pain, migraine, andother types of headaches.
 20. (canceled)
 21. A method of preventing ortreating a condition that is associated with the aberrant expressionand/or aberrant activation of a vanilloid receptor, comprisingadministering an effective amount of a composition of claim 16 to asubject in need thereof.
 22. A method of preventing or treating acondition that is selected from the group consisting of pain,inflammatory disease of the joints, neuropathies, HIV-relatedneuropathy, nerve injury, neurodegeneration, stroke, urinary bladderhypersensitivity, fecal urgency, gastro-esophageal reflux disease(GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease,cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus,prurigo, irritation of skin, eye or mucous membrane, hyperacusis,tinnitus, vestibular hypersensitivity, episodic vertigo, cardiacdiseases, hair growth-related disorders, rhinitis and pancreatitis,comprising administering an effective amount of a composition of claim16 to a subject in need thereof.
 23. The method of claim 22, wherein thecondition is pain, which is or which is associated with a conditionselected from the group consisting of osteoarthritis, rheumatoidarthritis, ankylosing spondylitis, diabetic neuropathic pain,post-operative pain, dental pain, non-inflammatory musculoskeletal pain,visceral pain, migraine, and other types of headaches.
 24. The method ofclaim 22, wherein the urinary bladder hypersensitivity is selected fromthe group consisting of urinary incontinence, cystitis, stomach duodenalulcer, irritable bowel syndrome (IBS), and inflammatory bowel disease(IBD).
 25. The method of claim 22, wherein the cardiac disease ismyocardial ischemia.
 26. The method of claim 22, wherein the hairgrowth-related disorder is effluvium or alopecia.
 27. The method ofclaim 23, wherein the non-inflammatory musculoskeletal pain is selectedfrom the group consisting of fibromyalgia, myofascial pain syndrome, andback pain.